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Gili Kenet

gili.kenet@sheba.health.gov.il

Journal articles

2009
 
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PMID 
G Young, S Becker, C Düring, F Friedrichs, N Goldenberg, G Kenet, M Manco-Johnson, C Scheffold, U Nowak-Göttl (2009)  Influence of the factor II G20210A variant or the factor V G1691A mutation on symptomatic recurrent venous thromboembolism in children: an international multicenter cohort study.   J Thromb Haemost 7: 1. 72-79 Jan  
Abstract: OBJECTIVE: To determine the relative importance of the factor (F) II G20210A or FV G1691A mutations as risk factors or predictors for fatal/non-fatal recurrent venous thromboembolism (VTE) in children. METHODS: In the present cohort, the rate of VTE recurrence and the time to recurrence in relation to FII, FV, age, and sex was determined in consecutively enrolled patients with VTE aged newborn to <or=18 years carrying the FII (n = 64) or FV (n = 194) mutation. 158 children with VTE without thrombophilia served as controls. Patients were followed for a median of 58 months. Data were pooled across participating sites to increase power and to enhance the generalizability of the data. Incidence rates were given as events per 1000 person-years. RESULTS: Of the 416 children enrolled, 44 had recurrent VTE at a median of 12 months following VTE onset. The overall incidence rate of recurrence was 19.8, 57.9 in patients with the FII variant, 17.9 for FV carriers, and 11.8 in the control cohort. When comparing FII patients, FV children and the control cohort multivariate analysis (Cox regression) adjusted for age and sex showed that the FII variant (hazard ratio 2.6; 95% confidence interval 1.1-5.9) influenced the hazard for recurrent VTE. CONCLUSIONS: Based on multivariate analysis, the presence of the FII variant was associated with an increased risk of VTE recurrence.
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Michal J Simchen, Gal Goldstein, Aaron Lubetsky, Tzipi Strauss, Eyal Schiff, Gili Kenet (2009)  Factor v Leiden and antiphospholipid antibodies in either mothers or infants increase the risk for perinatal arterial ischemic stroke.   Stroke 40: 1. 65-70 Jan  
Abstract: BACKGROUND AND PURPOSE: The objective was to investigate the role of infant and maternal thrombophilia in a cohort of mothers and infants presenting with perinatal arterial ischemic stroke. METHODS: Forty-seven infants with clinically and radiologically confirmed perinatal arterial ischemic stroke underwent thrombophilia workup: factor V Leiden (FVL), PII20210A mutation, Methylene-tetrahydrofolate reductase 677T polymorphism, protein C, protein S, antithrombin, FVIII, and antiphospholipid antibodies. Thrombophilia data were available for 23 mother-infant pairs and compared with control populations to evaluate the risk for PAS. RESULTS: Thirty of 47 (64%) infants and 15 of 22 mothers (68%) had evidence of thrombophilia. In 18 of 23 (78%) mother-infant pairs, there was at least 1 thrombophilic risk factor, but 15 pairs were mismatched in pathology. Among infants, FVL, protein C deficiency, and presence of antiphospholipid antibodies prevailed (OR, 4.2; 95% CI, 1.5-11.3; OR, 12.2; 95% CI, 2.5-59.9; OR, 4.1; 95% CI, 1.4-12.2, respectively). Interestingly FVL prevailed in almost one-third of mothers (OR, 8.5; 95% CI, 4.1-17.5) and 18% of mothers had antiphospholipid antibodies (OR, 3.8l; 95% CI, 1.5-10.0). CONCLUSIONS: Maternal and neonatal thrombophilia, especially presence of FVL or antiphospholipid antibodies, may be important in the pathogenesis of perinatal arterial ischemic stroke. The nature of thrombophilic mother-infant risk potential interactions warrants further investigation.
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2008
 
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Gili Kenet, Tzipi Strauss, Chaim Kaplinsky, Gideon Paret (2008)  Hemostasis and thrombosis in critically ill children.   Semin Thromb Hemost 34: 5. 451-458 Jul  
Abstract: Patients in the pediatric intensive care unit (PICU) often suffer from a variety of pathophysiologic conditions that are associated with abnormal hemostasis. Bleeding is a major complication of any surgery or trauma, thus patients with inherited or acquired coagulopathies or those experiencing massive trauma or undergoing major (especially cardiac) operations present a special challenge to the ICU experts as well as to the hematologist. Awareness of thromboembolic events in the pediatric population has been increasing in the past few years mainly due to improvement in diagnostic tools, advances in new therapy and procedures, together with an increased index of suspicion. Young infants are at greater risk for either bleeding or thromboembolic events, due to lower concentration of vitamin K-dependent procoagulant clotting factors, reduced thrombin potential, and altered fibrinolytic pathway with low levels of the coagulation inhibitors. The combination of infection, hypotension, acidosis, and release of activated substances, such as tumor necrosis factor, is common after severe trauma or in seriously ill ICU patients and often leads to disseminated intravascular coagulation, which may be complicated either by bleeding or thrombosis. The conditions, risk factors, and therapeutic options available for critically ill PICU patients are discussed in this review.
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U Nowak-Göttl, C Bidlingmaier, A Krümpel, L Göttl, G Kenet (2008)  Pharmacokinetics, efficacy, and safety of LMWHs in venous thrombosis and stroke in neonates, infants and children.   Br J Pharmacol 153: 6. 1120-1127 Mar  
Abstract: Since the early nineties it has been shown that low molecular weight heparin (LMWH) has significant advantages over unfractionated heparin and oral anticoagulants for both the treatment and the prevention of thrombosis, not only in adults, but also in children. The present review was based on an 'EMBASE', 'Medline' and 'PubMed' search including literature published in any language since 1980 on LMWH in neonates, infants and children. It included paediatric pharmacokinetic studies, the use of LMWH in children with venous thrombosis, LMWH administration in paediatric patients with ischaemic stroke, and its use in order to prevent symptomatic thromboembolism in children at risk. An increasing rate of off-label use of LMWH in children has been reported, showing that LMWHs offer important benefits to children with symptomatic thromboembolic events and poor venous access. Two well-conducted pharmacokinetic studies in this age group showed that neonates and younger infants require higher LMWH doses than older children to achieve the targeted anti-Xa levels, due to an increased extra vascular clearance. Recurrent symptomatic thromboses under LMWH occur in approximately 4% of children treated for venous thrombosis, and in 7% of children treated for stroke; major bleed was documented in 3% of children with therapeutic target LMWH anti-Xa levels, whereas minor bleeding was reported in approximately 23% of children receiving either therapeutic or prophylactic doses, respectively. Further randomized controlled trials are recommended to evaluate the optimum duration and application for different LMWH indications in children.
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G Kenet, E Ezra, S Wientroub, D M Steinberg, N Rosenberg, D Waldman, S Hayek (2008)  Perthes' disease and the search for genetic associations: collagen mutations, Gaucher's disease and thrombophilia.   J Bone Joint Surg Br 90: 11. 1507-1511 Nov  
Abstract: The role of heritable thrombophilic risk factors in the pathogenesis of the Perthes' disease is controversial. The clinical and radiological findings of Perthes' disease may be indistinguishable from those of Gaucher's disease, and the most common Jewish N370S Gaucher mutation is threefold greater in patients with Perthes' disease. Familial osteonecrosis of the femoral head is associated with variant mutations of collagen type II (COL2A1 mutations). We therefore studied the potential role of genetic thrombophilia and the Gaucher and COL2A1 mutations in children with Perthes' disease. Genomic DNA of 119 children with radiologically-confirmed Perthes' disease diagnosed between 1986 and 2005 was analysed for the thrombophilic polymorphisms Factor V Leiden, 677T-MTHFR and FIIG20210A. The results were compared with those of a group of 276 children without Perthes' disease. DNA was also analysed for the Gaucher mutations N370S, G insertion (84GG), L444P, Intron 2 (IVS2+1G>A) and R496H. Enzymic assays confirmed the Gaucher disease status. Collagen (COL2A1) mutations of the 12q13 gene were also analysed. The prevalence of thrombophilic markers was similar among the 119 patients with Perthes' disease and the 276 control subjects. The prevalence of the Gaucher mutation was consistent with Israeli population carriership data and did not confirm an earlier-claimed association with Perthes' disease. All 199 patients were negative for the studied COL2A1 mutations. We found no genetic association between Perthes' disease and either Gaucher's disease or COL2A1 mutations or increased genetic thrombophilia among our patients compared with the control group. A systematic review of case-control studies suggested that there was a positive association between Perthes' disease and Factor V Leiden. The impact of this association upon the disease, although not consistent across the studies, remains unclear.
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Gili Kenet, Uri Martinowitz (2008)  Single-dose recombinant activated factor VII therapy in hemophilia patients with inhibitors.   Semin Hematol 45: 2 Suppl 1. S38-S41 Apr  
Abstract: Recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) is well established as an effective hemostatic agent for the management of hemorrhage in hemophilia patients with inhibitors. Its use in prophylaxis is currently being investigated. On-demand treatment schedules usually involve multiple bolus doses of 90 to 120 microg/kg administered every 2 to 3 hours, but recent evidence from randomized controlled trials suggests that the use of higher single doses is equally safe and effective when used for the home treatment of hemarthroses. Consequently, the use of a single dose of 270 microg/kg rFVIIa for the treatment of bleeds in inhibitor patients has recently been approved by the European Medicines Agency (EMEA). Such high-dose regimens may overcome the rapid clearance rate observed in pediatric patients, and may be more convenient for patients with poor venous access. It also has been suggested that individually tailored single-dose therapies might be beneficial in selected groups of patients, although proper monitoring of such patients is advised. Further research should contribute towards more effective dose optimization of rFVIIa in hemophilic inhibitor patients.
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T Abshire, G Kenet (2008)  Safety update on the use of recombinant factor VIIa and the treatment of congenital and acquired deficiency of factor VIII or IX with inhibitors.   Haemophilia 14: 5. 898-902 Sep  
Abstract: Recombinant factor VIIa (rFVIIa, NovoSeven) has been licensed for treatment of haemophilia with inhibitors in Europe since 1996 and in North America since 1999. Overall, approximately 1.5 million doses have since been administered. Safety data from licensure to April 2003 revealed 25 thromboembolic (TE) adverse events (AE) from over 700 000 doses given, a remarkably low incidence of TE events. Recent reports have cited a higher prevalence of TE events with rFVIIa use, especially when used off-label. This report reviews the TE and fatal events with use of rFVIIa for congenital and acquired haemophilia A or B from May 2003 to December 2006. Approximately 800 000 standard doses of rFVIIa have been administered during this time frame. All clinical trials, spontaneous and solicited reports, as well as a detailed literature review, were included in the data analysis. There were a total of 30 TE events and 6 TE-associated fatal events. Spontaneous reports captured 14/71 (20%) TE/AE and 2/34 TE-associated/total fatal events. From solicited reports, 5/40 (12.5%) were associated with a TE and 1/32 TE-associated fatal events. Literature review revealed 11/19 (58%) TE events and 3/6 TE-associated fatal events. Despite the use of high-dose rFVIIa (270 mug kg(-1)) in some clinical trials and registries, rFVIIa appears safe, when used for congenital and acquired haemophilia. The prevalence of TE associated with rFVIIa use is less than 4/100 000 and a TE-associated fatal event is also extremely rare. However, use of rFVIIa for off-label indications should continue to be monitored closely via clinical trials and carefully designed registries.
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Herbertson, Kenet (2008)  Applicability and safety of recombinant activated factor VII to control non-haemophilic haemorrhage: investigational experience in 265 children.   Haemophilia Apr  
Abstract: Experience of recombinant activated factor VII (rFVIIa, NovoSeven((R)); Novo Nordisk A/S, Bagsvaerd, Denmark) to control haemorrhage in non-haemophilic children is limited. The object of this study was to examine the applicability and safety of rFVIIa amongst a group of non-haemophilic paediatric subjects. Details of all non-haemophilic children </=16 years receiving rFVIIa whose data were recorded in the investigational, internet-based registry, haemostasis.com were analysed. A total of 265 children (mean age 7.7 years) were treated with rFVIIa; the median dose administered was 78.4 mug kg(-1) body weight (range 9.0-393.4) and the median total dose received 100.0 mug kg(-1) body weight (range 10.9-1341.2). Therapeutic areas included surgery (34.5%), coagulopathy (including thrombocytopenia; 29.0%), spontaneous bleeding (17.2%), trauma (8.4%) and intracranial haemorrhage (4.5%). Two patients experienced thromboembolic events following administration of rFVIIa. Thirty-nine patients died on account of haemorrhage or complications relating to their underlying condition; neither the thromboembolic events nor the deaths were related to rFVIIa administration. Bleeding stopped in 118/237 (49.8%), markedly decreased in 54/237 (22.8%), decreased in 51/237 (21.5%), remained unchanged in 13/237 (5.5%) and increased in 1/237 (0.4%) patients. These results suggest that rFVIIa is safe and widely applicable in children to control non-haemophilic haemorrhage.
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Guy Young, Manuela Albisetti, Mariana Bonduel, Leonardo Brandao, Anthony Chan, Frauke Friedrichs, Neil A Goldenberg, Eric Grabowski, Christine Heller, Janna Journeycake, Gili Kenet, Anne Krümpel, Karin Kurnik, Aaron Lubetsky, Christoph Male, Marilyn Manco-Johnson, Prasad Mathew, Paul Monagle, Heleen van Ommen, Paolo Simioni, Pavel Svirin, Daniela Tormene, Ulrike Nowak-Göttl (2008)  Impact of inherited thrombophilia on venous thromboembolism in children: a systematic review and meta-analysis of observational studies.   Circulation 118: 13. 1373-1382 Sep  
Abstract: BACKGROUND: The aim of the present study was to estimate the impact of inherited thrombophilia (IT) on the risk of venous thromboembolism (VTE) onset and recurrence in children by a meta-analysis of published observational studies. METHODS AND RESULTS: A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2007 was conducted using key words in combination as both MeSH terms and text words. Citations were independently screened by 2 authors, and those meeting the inclusion criteria defined a priori were retained. Data on year of publication, study design, country of origin, number of patients/controls, ethnicity, VTE type, and frequency of recurrence were abstracted. Heterogeneity across studies was evaluated, and summary odds ratios and 95% CIs were calculated with both fixed-effects and random-effects models. Thirty-five of 50 studies met inclusion criteria. No significant heterogeneity was discerned across studies. Although >70% of patients had at least 1 clinical risk factor for VTE, a statistically significant association with VTE onset was demonstrated for each IT trait evaluated (and for combined IT traits), with summary odds ratios ranging from 2.63 (95% CI, 1.61 to 4.29) for the factor II variant to 9.44 (95% CI, 3.34 to 26.66) for antithrombin deficiency. Furthermore, a significant association with recurrent VTE was found for all IT traits except the factor V variant and elevated lipoprotein(a). CONCLUSIONS: The present meta-analysis indicates that detection of IT is clinically meaningful in children with, or at risk for, VTE and underscores the importance of pediatric thrombophilia screening programs.
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2007
 
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PMID 
Barbara Voetsch, Richard C Jin, Charlene Bierl, Kelly S Benke, Gili Kenet, Paolo Simioni, Filomena Ottaviano, Benito P Damasceno, Joyce M Annichino-Bizacchi, Diane E Handy, Joseph Loscalzo (2007)  Promoter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene: a novel risk factor for arterial ischemic stroke among young adults and children.   Stroke 38: 1. 41-49 Jan  
Abstract: BACKGROUND AND PURPOSE: Plasma glutathione peroxidase (GPx-3)-deficiency increases extracellular oxidant stress, decreases bioavailable nitric oxide, and promotes platelet activation. The aim of this study is to identify polymorphisms in the GPx-3 gene, examine their relationship to arterial ischemic stroke (AIS) in a large series of children and young adults, and determine their functional molecular consequences. METHODS: We studied the GPx-3 gene promoter from 123 young adults with idiopathic AIS and 123 age- and gender-matched controls by single-stranded conformational polymorphism and sequencing analysis. A second, independent population with childhood stroke was used for a replication study. We identified 8 novel, strongly linked polymorphisms in the GPx-3 gene promoter that formed 2 main haplotypes (H1 and H2). The transcriptional activity of the 2 most prevalent haplotypes was studied with luciferase reporter gene constructs. RESULTS: The H2 haplotype was over-represented in both patient populations and associated with an independent increase in the risk of AIS in young adults (odds ratio=2.07, 95% CI=1.03 to 4.47; P=0.034) and children (odds ratio=2.13, 95% CI=1.23 to 4.90; P=0.027). In adults simultaneously exposed to vascular risk factors, the risk of AIS approximately doubled (odds ratio=5.18, 95% CI=1.82 to 15.03; P<0.001). Transcriptional activity of the H2 haplotype was lower than that of the H1 haplotype, especially after upregulation by hypoxia (normalized relative luminescence: 3.54+/-0.32 versus 2.47+/-0.26; P=0.0083). CONCLUSIONS: These findings indicate that a novel GPx-3 promoter haplotype is an independent risk factor for AIS in children and young adults. This haplotype reduces the gene's transcriptional activity, thereby compromising gene expression and plasma antioxidant and antithrombotic activities.
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Michal Zucker, Ariella Zivelin, Meytal Landau, Ophira Salomon, Gili Kenet, Frederic Bauduer, Michel Samama, Jacqueline Conard, Marie-Hélène Denninger, Abu-Samra Hani, Micheline Berruyer, Donald Feinstein, Uri Seligsohn (2007)  Characterization of seven novel mutations causing factor XI deficiency.   Haematologica 92: 10. 1375-1380 Oct  
Abstract: BACKGROUND AND OBJECTIVES: Factor XI (FXI) deficiency is a rare autosomal recessive disorder, the main manifestation of which is injury-related bleeding. The disorder is rare in most populations, but common among Jews in whom two mutations, E117X and F283L, account for 98% of cases. Other mutations, C38R and C128X, are prevalent in French Basques and Britons, respectively. Additional sporadic mutations have been described in most parts of the world. The objective of this study was to identify the mutations in 15 unrelated FXI-deficient patients and characterize missense mutations by expression in baby hamster kidney (BHK) cells. DESIGN AND METHODS: Clinical and laboratory information and DNA samples were obtained from the patients and mutations were identified by sequencing. Missense mutations were expressed in BHK cells and their effect on FXI secretion and dimerization was assessed using enzyme-linked immunosorbent assay and immunoblotting. RESULTS: Of 16 mutations detected, seven are novel including two deletions, one splice site and four missense mutations. Expression of the four novel missense mutations (C58Y, Y427C, C527Y and V20A) in cells revealed no secretion of FXI-C58Y, Y427C and C527Y and secretion of only 22% of normal in the medium for FXI-V20A. Secretion of FXI from BHK cells harboring a previously reported E297K substitution cells was also impaired (4.5% of wild-type). Homodimerization was normal for all five mutants. INTERPRETATION AND CONCLUSIONS: Defective homodimerization of FXI was previously recognized as a major mechanism for defective secretion of FXI from producing cells. In this study, five FXI missense mutations (four novel) were associated with impaired secretion albeit normal dimerization, underscoring the existence of other mechanisms for defective secretion.
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Gili Kenet, Fenella Kirkham, Thomas Niederstadt, Achim Heinecke, Dawn Saunders, Monika Stoll, Benjamin Brenner, Christoph Bidlingmaier, Christine Heller, Ralf Knöfler, Rosemarie Schobess, Barbara Zieger, Guillaume Sébire, Ulrike Nowak-Göttl (2007)  Risk factors for recurrent venous thromboembolism in the European collaborative paediatric database on cerebral venous thrombosis: a multicentre cohort study.   Lancet Neurol 6: 7. 595-603 Jul  
Abstract: BACKGROUND: The relative importance of previous diagnosis and hereditary prothrombotic risk factors for cerebral venous thrombosis (CVT) in children in determining risk of a second cerebral or systemic venous thrombosis (VT), compared with other clinical, neuroimaging, and treatment variables, is unknown. METHODS: We followed up the survivors of 396 consecutively enrolled patients with CVT, aged newborn to 18 years (median 5.2 years) for a median of 36 months (maximum 85 months). In accordance with international treatment guidelines, 250 children (65%) received acute anticoagulation with unfractionated heparin or low-molecular weight heparin, followed by secondary anticoagulation prophylaxis with low-molecular weight heparin or warfarin in 165 (43%). RESULTS: Of 396 children enrolled, 12 died immediately and 22 (6%) had recurrent VT (13 cerebral; 3%) at a median of 6 months (range 0.1-85). Repeat venous imaging was available in 266 children. Recurrent VT only occurred in children whose first CVT was diagnosed after age 2 years; the underlying medical condition had no effect. In Cox regression analyses, non-administration of anticoagulant before relapse (hazard ratio [HR] 11.2 95% CI 3.4-37.0; p<0.0001), persistent occlusion on repeat venous imaging (4.1, 1.1-14.8; p=0.032), and heterozygosity for the G20210A mutation in factor II (4.3, 1.1-16.2; p=0.034) were independently associated with recurrent VT. Among patients who had recurrent VT, 70% (15) occurred within the 6 months after onset. CONCLUSION: Age at CVT onset, non-administration of anticoagulation, persistent venous occlusion, and presence of G20210A mutation in factor II predict recurrent VT in children. Secondary prophylactic anticoagulation should be given on a patient-to-patient basis in children with newly identified CVT and at high risk of recurrent VT. Factors that affect recanalisation need further research.
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Y Maor, P Calès, D Bashari, G Kenet, A Lubetsky, J Luboshitz, J M Schapiro, G Pénaranda, S Bar-Meir, U Martinowitz, P Halfon (2007)  Improving estimation of liver fibrosis using combination and newer noninvasive biomarker scoring systems in hepatitis C-infected haemophilia patients.   Haemophilia 13: 6. 722-729 Nov  
Abstract: Non-invasive biomarkers have gained popularity for estimating fibrosis stage. In our hepatitis C-infected haemophilia patients, Fibrotest (FT) correctly identified clinically advanced or minimal liver disease. More accurate tests, like the FibroMeters, have recently been validated. The aim of the study was to improve the estimation of liver fibrosis in hepatitis C-infected haemophiliacs using a combination of biomarkers and FibroMeters. One hundred and thirty-two hepatitis C-infected haemophilia patients (124 male, mean age: 39+/-14 years) were evaluated. The following biomarkers were used: FT, AST-to-platelet ratio index (APRI), Forns index, hyaluronic acid and FibroMeter. We applied a published algorithm suggesting that if FT is in concordance with APRI and/or Forns score, then the FT concurs with liver biopsy for estimation of fibrosis. Concordance of three or more biomarkers was present in 43.2% (57/132) of the patients. This high discordance rate was mainly because of indeterminate scores. Significant fibrosis (F2-F4) was estimated at 34.8% (46/132) and 37.9% (50/132) by the FT and FibroMeter respectively. The discordance rate between the FT and FibroMeter was 16.7% (22/132), (P<0.01 vs. other biomarkers). Using the algorithm, liver histology could be confidently estimated in 69.7% (92/132) of the patients. Concordance between the FT and FibroMeter in those patients who met the terms of the algorithm was 90.2% (83/92). Discordance between biomarkers is significant, and is mainly because of biomarkers with indeterminate results. The concordance rate between FT and FibroMeter is higher compared with the other biomarkers. Practical combination of tests may potentially limit the need of liver biopsy in the majority of haemophilia patients.
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2006
 
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Gili Kenet (2006)  High-dose recombinant factor VIIa therapy in hemophilia patients with inhibitors.   Semin Hematol 43: 1 Suppl 1. S108-S110 Jan  
Abstract: Recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) is well established as an effective hemostatic agent for the management and prophylaxis of hemorrhage in hemophilia patients with inhibitors. Treatment schedules usually involve multiple bolus doses of 90 to 120 microg/kg administered every 2 to 3 hours, but recent evidence suggests that the use of higher doses might be justified. Such high-dose regimens may overcome the rapid clearance rate observed in pediatric patients, and may be more convenient for patients with poor venous access. It has been suggested that individually tailored high-dose therapies might be beneficial in selected groups of patients, although careful monitoring of such patients is advised. Thrombelastography has demonstrated considerable success in this regard, allowing accurate assessment of both hemostatic efficacy and individual response to rFVIIa. To date, no safety issues associated with high-dose rFVIIa have been identified. However, it is hoped that further research will support these favorable observations and thus contribute towards more effective dose optimization of rFVIIa in hemophilic inhibitor patients.
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Shoshana Revel-Vilk, Gili Kenet (2006)  Thrombophilia in children with venous thromboembolic disease.   Thromb Res 118: 1. 59-65 07  
Abstract: Venous thromboembolic events (VTEs) in children are usually associated with underlying clinical conditions such as central venous line, cancer and cardiac diseases. The objective of this review is to present the importance of thrombophilia to the occurrence of childhood VTE. The reported prevalence of thrombophilia in children with VTE varies extremely between 10% and 78% in different registries. The variation in the reported prevalence most probably reflects differences in the clinical characteristics of the children studied and differences in study designs. The initial management of children with thrombophilia and VTE is similar to those individuals who do not have a specific inherited thrombophilic risk factor, except in the rare events of homozygous deficiencies of prothrombotic coagulation proteins. The impact of thrombophilic markers on long-term therapy and outcome of children with VTE has not been completely clarified. According to the current guidelines for thrombophilia, all children with VTE should be tested for a full panel of genetic and acquired prothrombotic traits. However, re-evaluation of co-morbid risk factors other than thrombophilic markers and careful consideration of the prognostic value of thrombophilic markers might help to change future attitude from the rigidity of current guidelines to more rational schemes.
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Y Levy-Shraga, A Maayan-Metzger, A Lubetsky, B Shenkman, J Kuint, U Martinowitz, G Kenet (2006)  Platelet function of newborns as tested by cone and plate(let) analyzer correlates with gestational Age.   Acta Haematol 115: 3-4. 152-156  
Abstract: The issue of platelet function in infants and neonates is of interest, and current data are debatable. A new method for assessing platelet function involves using the cone and plate(let) analyzer (CPA), applicable for small (0.2 ml) whole blood volumes. We used polystyrene surface-coated plates to evaluate cord blood neonatal platelet function under flow. One hundred and sixty full-term and 29 preterm infants born at the Sheba Medical Center between March 2003 and January 2004 were evaluated for platelet adhesion measured as surface coverage (SC; the percentage of total area covered by platelets) and platelet aggregation, defined as the average size (AS) of the aggregates. Platelets from preterm infants displayed less platelet adhesion than did those from full-term infants. Platelet SC correlated with gestational age in all infants (p < 0.05), and both groups exhibited similar aggregation (AS). AS values, however, were significantly lower than the normal adult range in our laboratory. Infants born to mothers with pregnancy-induced hypertension displayed significantly lower SC. No association was found between CPA and postnatal complications. Conclusion: CPA provides a rapid, feasible option for testing platelet function in neonates. Its potential predictive value deserves further attention, and more extensive studies are warranted.
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Y Maor, D Bashari, G Kenet, S Lalezari, A Lubetsky, J Luboshitz, J M Schapiro, B Avidan, S Bar-Meir, U Martinowitz (2006)  Hepatitis C at the israeli national hemophilia center.   Haemophilia 12: 1. 68-74 Jan  
Abstract: Haemophilia patients who received non-virucidally treated large pool clotting factors before 1987 have a high rate of chronic hepatitis C viral infection (HCV). Some patients are coinfected with HIV. Haemophilia patients and other coagulation disorders were treated at one centre since the beginning of the 1970, and the Israeli National Hemophilia Center (INHC) was officially founded in 1987. To characterize patients with HCV as well as patients with HCV/HIV coinfection at the INHC. Patients with haemophilia and other coagulation disorders positive for HCV antibodies were evaluated between 2001 and 2004. Demographic data, type and severity of coagulation disorder, frequency of coagulation factor usage and treatment with concentrated clotting factors prior to 1987 were recorded. Liver enzymes, viral load, genotype and data supporting advanced liver disease were evaluated. About 179 of 239 haemophilia patients (75%) tested positive for anti-HCV antibodies. Our cohort consisted of 165 patients in whom clinical, biochemical and virological data were available. About 117 patients had active HCV infection with HCV-RNA-positive, and 27 were HCV/HIV coinfected. Twenty-one patients (13%) persistently tested HCV-RNA-negative, hence were considered to clear their HCV infection. There was no former USSR immigrants among HCV/HIV coinfected compared with HCV-infected or HCV-RNA-negative groups (0 vs. 30% and 38%, respectively; P < 0.001). HCV-RNA-negative patients used concentrated coagulation factor less frequently than HCV or HCV/HIV-infected patients (48% vs. 73%; P = 0.023, and 48% vs. 74%; P = 0.043, respectively). The use of concentrated clotting factors before 1987 was significantly more frequent in HCV/HIV than in either HCV-infected or HCV-RNA-negative patients (96% vs. 49% and 48%, respectively; P < 0.001). Compared with HCV/HIV subjects, patients with HCV monoinfection were characterized by a higher proportion of infection with genotype 1 (80% vs. 61%; P = 0.027). The rate of persistently normal liver enzymes in these patients was higher (24% vs. 7%; P = 0.05) than in the HCV/HIV-coinfected patients. Advanced liver disease was significantly more common in patients with HCV/HIV-coinfection than in HCV-monoinfected patients (11% vs. 3%; P = 0.045). The majority of haemophilia patients are infected with HCV. Viral clearance occurred in a minority of these patients. HCV monoinfected and HCV/HIV coinfected differ clinically and prognostically.
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Y Maor, D Bashari, G Kenet, A Lubetsky, J Luboshitz, J M Schapiro, G Pénaranda, S Bar-Meir, U Martinowitz, P Halfon (2006)  Non-invasive biomarkers of liver fibrosis in haemophilia patients with hepatitis C: can you avoid liver biopsy?   Haemophilia 12: 4. 372-379 Jul  
Abstract: Liver biopsy remains the gold standard for the evaluation of fibrosis despite its risks and limitations, especially in haemophilia patients. Recently, non-invasive biomarkers have been used to assess histological features. The most thoroughly evaluated biomarker is the FibroTest (FT) (AUROC 0.80 for fibrosis stages F2F3F4 vs. F0F1). To estimate liver fibrosis in haemophilia patients infected with hepatitis C (HCV) using non-invasive biomarkers without liver biopsy. One hundred and thirty-two haemophilia patients (124 male, mean age 38 +/- 14 years) with anti-HCV antibodies were evaluated. These patients were stratified into several groups: patients with features of advanced liver disease - seven, persistently HCV RNA-negative - 21, persistently normal liver function tests (LFTs)- 24, HCV/HIV co-infected - 27. The following biomarkers of fibrosis were used: FT, AST-to-platelet ratio index (APRI), Forns index, age-platelet index and hyaluronic acid. The obtained scores were correlated with the clinical features of the patients. Estimated by the FT, the distribution of the stage of fibrosis in the 132 patients was F0F1 = 65% (86/132), F2 = 5% (7/132), F3 = 13% (17/132) and F4 = 17% (22/132). Using FT, all patients with clinical suspicion of advanced liver disease were classified as F3F4, whereas patients with persistently HCV RNA-negative were all classified as F0F1. Twenty-one per cent (5/24) of the patients with persistently normal LFTs had fibrosis stage F3F4. The proportion of F3F4 among HCV/HIV co-infected patients was significantly higher than among HCV mono-infected (52% vs. 33%; P = 0.05). Concordance of three or more biomarkers was present in 43% (57/132) of the patients. Liver biopsy could be avoided in 70% (92/132) using a practical assumption that if FT is in concordance with APRI and/or Forns, then we may confidently rely on the biomarker. Concordance rate for patients with presumably advanced or minimal liver disease was excellent (100% and 95% respectively). In our HCV-infected haemophilia patients, FT correctly identified clinically advanced or minimal liver disease. Discordance among the various biomarkers of fibrosis was considerate; nevertheless, practical combination of FT, APRI, and Forns may predict stage of fibrosis with accuracy, potentially avoiding liver biopsy in the majority of the patients.
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Y Berkun, S Padeh, J Barash, Y Uziel, L Harel, M Mukamel, S Revel-Vilk, G Kenet (2006)  Antiphospholipid syndrome and recurrent thrombosis in children.   Arthritis Rheum 55: 6. 850-855 Dec  
Abstract: OBJECTIVE: Few studies have addressed antiphospholipid syndrome (APS) among children. Our aims were to analyze the clinical and laboratory manifestations in a pediatric APS cohort and to assess the influence of inherited thrombophilia factors on the outcome of children with APS. METHODS: This was a multicenter study of children with APS who had no previous systemic autoimmune disease. We retrospectively reviewed their clinical and laboratory data, including hereditary thrombophilic deficits and outcomes. RESULTS: The cohort comprised 28 patients (17 females, mean +/- SD age at onset 10.6 +/- 6.1 years). The most common initial manifestations of APS were venous thrombosis, stroke, and thrombocytopenia. Lupus anticoagulant was detected in 96% of those tested. After a mean +/- SD followup of 5.7 +/- 4.8 years, 16 children (57.1%) had central nervous system disease, 9 exhibited hematologic involvement, and 5 (all females) had systemic lupus erythematosus (SLE). None had renal, heart, or new skin disease. Seven of 24 patients exhibiting vascular thrombotic events had recurrences. Infants with perinatal stroke had monophasic disease, and other manifestations of APS did not develop later. Hereditary thrombophilia was more common in children who experienced a single episode of APS (8 [53.3%] of 15 patients) than in those who experienced recurrences (2 [28.6%] of 7 patients). However, only 2 patients in the latter group (28.6%) received anticoagulants after the first manifestation, compared with 12 (70.6%) of the 17 patients without recurrences. CONCLUSION: APS in children has unique features. SLE may develop in a significant percentage of girls presenting with APS. Hereditary thrombophilia did not predict recurrent thrombosis, whereas the preventive impact of anticoagulant treatment following the first thrombotic event was noteworthy.
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A Maayan-Metzger, J Kuint, A Lubetsky, Boris Shenkman, R Mazkereth, G Kenet (2006)  Maternal selective serotonin reuptake inhibitor intake does not seem to affect neonatal platelet function tests.   Acta Haematol 115: 3-4. 157-161  
Abstract: Recently, concerns have been raised regarding the potential impairment of neonatal platelet function and the potential risk of bleeding in neonates born to mothers treated with selective serotonin reuptake inhibitors (SSRI). Our aim was to test whether the platelet function of neonates born to SSRI-treated mothers was impaired when compared to non-SSRI-exposed neonates. In a single-center prospective study, platelet function was evaluated using a cone and platelet analyzer (CPA) device and compared between mother-infant pairs as well as normal non-SSRI-exposed infants. Twenty-seven SSRI-exposed and 27 non-SSRI-exposed full-term neonates and their 23 mothers were tested. No correlation was found between SSRI exposure among either neonates or mothers and parameters of surface coverage (SC) and average size (AS), manifesting platelet function as tested by CPA. SC was similar among SSRI-exposed babies as compared to those in the control group, whereas the size of platelet aggregates (AS) was higher among controls. Neither maternal diseases nor SSRI intake were associated with impaired platelet function and lower SC values, nor were any perinatal conditions. None of the babies suffered from bleeding. We conclude that maternal SSRI therapy does not impair whole-blood CPA-tested platelet function of healthy full-term neonates.
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Gili Kenet, Ulrike Nowak-Göttl (2006)  Fetal and neonatal thrombophilia.   Obstet Gynecol Clin North Am 33: 3. 457-466 Sep  
Abstract: Thrombophilia of the fetus and neonate may contribute to higher prevalence of perinatal thrombosis. Due to the potential interaction between thrombophilic risk factors of the neonate and maternal thrombophilia and placental vasculopathy, we recommend thrombophilia assessment be performed in any child and in the mother in case of perinatal thrombosis. Further attention and larger prospective studies are required to establish the role of thrombophilic risk factors in the pathogenesis of any other perinatal complications.
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PMID 
Khan Kavakli, Mike Makris, Bulent Zulfikar, Elizabeth Erhardtsen, Zvi S Abrams, Gili Kenet (2006)  Home treatment of haemarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. A multi-centre, randomised, double-blind, cross-over trial.   Thromb Haemost 95: 4. 600-605 Apr  
Abstract: The aim was to evaluate the efficacy and safety of two recombinant factor VIIa (rFVIIa) dose regimens for treating haemarthroses in patients with congenital haemophilia A or B and inhibitors. This was a multicentre, randomised, cross-over, double-blind trial. Patients were randomly allocated to treat a first joint bleeding episode with one 270 microg/kg rFVIIa dose followed by two doses of placebo at 3-hour intervals and a second joint bleed with three single doses of 90 microg/kg rFVIIa at 3-hour intervals, or vice versa. Efficacy was evaluated using a novel and robust treatment response-rating scale based on patient-assessment of pain and joint mobility. Outcome was rated at different timepoints, and an effective or ineffective treatment response was determined. Treatment "preference" was defined as effective treatment with one regimen and ineffective with the other. Patients with equally effective or ineffective treatments had no "preference". Treatment was rated as effective for 65% of patients using the 270 microg/kg dose versus 70% for the 90 microg/kg x 3 regimen. An equal "preference" was noted for the two regimens (21% for each; p = 0.637); most patients (58%) had no "preference". 37/42 bleeding episodes (88%) were successfully treated with rFVIIa; additional haemostatic medications were administered for five episodes. No safety issues were identified. Administration of rFVIIa as a single 270 microg/kg dose to treat haemarthroses in patients with haemophilia and inhibitors was at least as efficacious and safe as the 90 microg/kg x 3 regimen.
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2005
 
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Aviva Fattal-Valevski, Gili Kenet, Michael J Kupferminc, Ronit Mesterman, Yael Leitner, Eli Rimon, Shaul Harel, Avi Hassner (2005)  Role of thrombophilic risk factors in children with non-stroke cerebral palsy.   Thromb Res 116: 2. 133-137 12  
Abstract: BACKGROUND: Thrombophilic risk factors play an important role in the pathogenesis of perinatal stroke and resultant cerebral palsy (CP). The association between thrombophilia and CP caused by etiologies other than stroke is undetermined. METHODS: We assessed three genetic thrombophilic markers (mutation of Factor V Leiden [FV G1691A], 677T polymorphism of thermolabile methylenetetrahydrofolate reductase [MTHFR] and G20210A mutation of the prothrombin gene) in 49 pediatric patients with non-stroke CP and compared the findings with 118 apparently healthy controls. CP in the study group was due to periventricular leukomalacia (n=27), intraventricular hemorrhage (n=9), hypoxic ischemic encephalopathy (n=4), prematurity with no apparent complication (n=8) and intrauterine growth retardation (n=1). Twenty-five children had spastic diplegia, 20 had spastic quadriplegia and 4 had spastic hemiplegia. CP was graded as being severe in 26 children (53%). RESULTS: No significant difference in the prevalence of thrombophilic risk factors was found between the study and control groups. Twelve study children (24.5%) had at least one of the three thrombophilic mutations compared with 27 controls (23%). There was no significant difference in the prevalence of each thrombophilic risk factor in the various etiologic groups and in the subgroups of mild/severe CP and the control group. CONCLUSION: These findings support the notion that thrombophilia neither contributes to the occurrence nor affects the clinical outcome and severity of non-stroke CP.
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Sam Schulman, Geir E Tjønnfjord, Richard Wallensten, Uri Martinowitz, Gill Kenet (2005)  Continuous infusion of recombinant factor VIIa for surgery in patients with deficiency of factor VII.   Thromb Haemost 94: 6. 1177-1180 Dec  
Abstract: The administration of recombinant activated factor VII (rFVIIa) by continuous infusion has provided a safe and convenient alternative to bolus injections in haemophiliacs with inhibitors, but it has only been reported in a single case with congenital factor VII (FVII) deficiency. The results of 12 consecutive surgical procedures in 7 patients with congenital FVII deficiency are reported here. rFVIIa was always given in continuous infusion,aiming at plasma FVII activity of 0.5 IU/mL. Treatment was given for 2 to 7 days with a mean total dose of 7.8 mg rFVIIa. Blood loss was as expected from the different types of procedures and the only thromboembolic complication was a superficial thrombophlebitis at the infusion site. This mode of substitution was therefore safe, effective and well tolerated.
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B Falk, S Portal, R Tiktinsky, L Zigel, Y Weinstein, N Constantini, G Kenet, A Eliakim, U Martinowitz (2005)  Bone properties and muscle strength of young haemophilia patients.   Haemophilia 11: 4. 380-386 Jul  
Abstract: PURPOSE: To evaluate bone properties, muscle strength and the relationship between the two, in young (7.0-17.7 years) haemophilia patients (h) and healthy boys (c). SUBJECTS: Twenty-seven boys with severe haemophilia and 33 healthy boys, of similar age, body mass, height, (mean +/- sd for h and c, respectively: 11.2 +/- 3.2 vs. 11.4 +/- 2.9 years, 42.6 +/- 16.6 vs. 41.6 +/- 17.3 kg, 145 +/- 18 vs. 146 +/- 17 cm) and pubertal stage according to secondary sex characteristics, volunteered for the study. all subjects were physically inactive (as determined by questionnaire). METHODS: Subjects performed isokinetic elbow and knee extension and flexion tests at two angular velocities (biodex system ii dynamometer). Bone properties were evaluated by qualitative ultrasound (sunlight omnisense), at the distal radius and tibial mid-shaft. H subjects received prophylactic factor viii treatment within the 24 h preceding testing. No test was performed in the presence of haemorrhage. RESULTS: Muscle strength was consistently higher in c compared with h, especially in the lower limbs (e.g. knee extension: 1.80 +/- 0.44 vs 1.48 +/- 0.53 N x m x kg(-1) body mass, respectively, p = 0.01). No differences were observed in tibial or radial speed of sound between groups. Correlations between muscle strength and bone properties were observed only in the lower limbs and only in c (r = 0.37-0.48). CONCLUSION: Muscle strength, especially lower limbs' strength, was lower in haemophilia patients compared with a matched, similarly inactive population of healthy boys. Nevertheless, at this age range, this relative weakness is not associated with inferior bone properties.
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N Rosenberg, H Hauschner, H Peretz, R Mor-Cohen, M Landau, B Shenkman, G Kenet, B S Coller, A A Awidi, U Seligsohn (2005)  A 13-bp deletion in alpha(IIb) gene is a founder mutation that predominates in Palestinian-Arab patients with Glanzmann thrombasthenia.   J Thromb Haemost 3: 12. 2764-2772 Dec  
Abstract: Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder caused by lack or dysfunction of alpha(IIb)beta3 in platelets. GT is relatively frequent in highly inbred populations. We previously identified a 13-bp deletion in the alpha(IIb) gene that causes in-frame deletion of six amino acids in three Palestinian GT patients. In this study, we determined the molecular basis of GT in all known Palestinian patients, examined whether Jordanian patients harbor the same mutations, analyzed whether there is a founder effect for the 13-bp deletion, and determined the mechanism by which the 13-bp deletion abolishes alpha(IIb)beta3 surface expression. Of 11 unrelated Palestinian patients, eight were homozygous for the 13-bp deletion that displayed common ancestry by haplotype analysis, and was estimated to have occurred 300-600 years ago. Expression studies in baby hamster kidney cells showed that substitution of Cys107 or Trp110 located within the deletion caused defective alpha(IIb)beta3 maturation. Substitution of Trp110, but not of Cys107, prevented fibrinogen binding. The other Palestinian patients harbored three novel mutations: G2374 deletion in alpha(IIb) gene, TT1616-7 deletion in beta3 gene, and IVS14: -3C --> G in beta3 gene. The latter mutation caused cryptic splicing predicting an extended cytoplasmic tail of beta3 and was expressed as dysfunctional alpha(IIb)beta(3). None of 15 unrelated Jordanian patients carried any of the described mutations.
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2004
 
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T Abshire, G Kenet (2004)  Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors.   J Thromb Haemost 2: 6. 899-909 Jun  
Abstract: Recombinant factor (rF)VIIa has been available to clinicians since 1996 and has an excellent safety record after almost three-quarters of a million doses have been administered. This paper will review the current clinical experience with rFVIIa dosing in acquired and congenital hemophilia with inhibitors and chronicle all spontaneous and clinical trial reports of thrombotic adverse events as of April 2003. Standard dosing of rFVIIa (90 micro g kg(-1)) allows binding of FVIIa to the surface of an activated platelet and can directly activate factor X in the absence of tissue factor. Experience with bolus dosing suggests that higher dosing (>200 micro g kg(-1)) may be more efficacious in treating hemophilia patients. Clinical trials are ongoing to validate this observation. Continuous infusion dosing may be efficacious for major surgery but high infusion rates (50 micro g kg(-1) h(-1)) might be needed. The relationship between dose of rFVIIa, amount of thrombin generated and measurable FVIIa level is still not known and perhaps newer testing which measures thrombin generation might be more advantageous. Relatively few thrombotic events have been associated with rFVIIa. Known factors predisposing to thrombosis were present in 20 of the 25 (80%) hemophilia patients who were reported spontaneously or who developed a thrombosis during a clinical trial. Additionally, thrombotic events have not increased despite a growing experience with higher dosing of rFVIIa.
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Benjamin Brenner, Eric F Grabowski, Margaretta Hellgren, Gili Kenet, Patricia Massicotte, Marilyn Manco-Johnson, Prasad Mathew, Wolfgang Muntean, Nicole Schlegel, Ulrike Nowak-Göttl (2004)  Thrombophilia and pregnancy complications.   Thromb Haemost 92: 4. 678-681 Oct  
Abstract: The implications of currently available data on the association of gestational vascular complications with thrombophilia are presented in this consensus report. Screening is recommended for women with the following previous complications: fetal loss including three or more first trimester loss, two or more second trimester loss, or any stillbirth; early, severe or recurrent preeclampsia and severe intrauterine growth restriction. Maternal antithrombotic therapy is currently evaluated in women with thrombophilia and previous complications.
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Gili Kenet, Dalia Waldman, Aharon Lubetsky, Nurit Kornbrut, Abdalla Khalil, Ariel Koren, Baruch Wolach, Aviva Fattal, Joseph Kapelushnik, Hannah Tamary, Joanne Yacobovitch, Eyal Raveh, Shoshana Revel-Vilk, Amos Toren, Benjamin Brenner (2004)  Paediatric cerebral sinus vein thrombosis. A multi-center, case-controlled study.   Thromb Haemost 92: 4. 713-718 Oct  
Abstract: The etiology and pathophysiology of cerebral sinus venous thrombosis (CSVT) in the paediatric population is still poorly understood, and the role of thrombophilic risk factors remains to be elucidated. In our multi-center case-controlled study we studied 46 patients with CSVT diagnosed from April 1996 to December 2003, consecutively referred for thrombophilia work-up. The results of thrombophilia screen were compared to 112 healthy paediatric controls. Anticoagulant therapy was applied according to treating physicians' decisions, and all cases were prospectively followed for a median of 4.1 years. Of 46 children, 8 had CSVT diagnosed in the neonatal period and therefore were analyzed separately. The prevalence of single thrombophilia markers and combinations of thrombophilic risk factors were similar among cases and controls. Among children with CSVT co-morbid systemic illness was present in most patients at diagnosis. Seven out of 8 children with idiopathic CSVT had thrombophilic risk factors as compared to 31/38 patients with co-morbid conditions. Anticoagulation was initiated in most patients, 11/46 patients continued therapy for a total of one year or more post event. Neither clinical presentation nor initial treatment decisions were affected by presence of thrombophilic risk factors in our study group. Thrombophilia prevalence was not increased in children with CSVT as compared to controls, however thrombophilia was more frequent among children with idiopathic CSVT. Thus, those selected patients would benefit most from thrombophilia work-up, required for long-term therapy considerations.
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2003
 
PMID 
G Kenet, A Lubetsky, J Luboshitz, U Martinowitz (2003)  A new approach to treatment of bleeding episodes in young hemophilia patients: a single bolus megadose of recombinant activated factor VII (NovoSeven).   J Thromb Haemost 1: 3. 450-455 Mar  
Abstract: Recombinant activated factor VII (rFVIIa, NovoSeven) represents an effective treatment for hemophilia patients with inhibitors, but no consensus as to the best dosing regimen exists. We assessed the efficacy and safety of a rFVIIa 'megadose' (300 micro g kg(-1) bolus) as treatment for bleeds in three young inhibitor patients. Of 114 bleeds, 95 responded to a single dose. Pain relief was faster and therapy duration significantly shorter than with continuous infusion (CI) regimens or standard boluses (90 micro g kg(-1) every 3 h). Rebleeding occurred in 9.6% of cases and 19/114 episodes required a second bolus injection. Although rFVIIa consumption per bleed (median: 300 micro g kg(-1)) was higher than with standard boluses (180-270 micro g kg(-1)), patients found single bolus administration more convenient than recurrent injections or CI. With two exceptions, no complications occurred within 3 h of treatment, despite high FVII:C levels (median: 27.4 U mL(-1); range: 19.8-54 U mL(-1)). Treatment of bleeds with a rFVIIa megadose in young inhibitor patients is effective and well tolerated.
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PMID 
G Kenet, S Hayek, M Mor, A Lubetsky, L Miller, N Rosenberg, R Mosheiff, M Itzchaki, D Elstein, S Wientroub, A Zimran (2003)  The 1226G (N370S) Gaucher mutation among patients with Legg-Calve-Perthes disease.   Blood Cells Mol Dis 31: 1. 72-74 Jul/Aug  
Abstract: Legg-Calve-Perthes disease (LCPD) is an avascular necrosis of the femoral head with an annual incidence of 5-15/100,000. The estimated incidence of Gaucher disease, a lysosomal recessive storage disease, is 1:850, with a carrier rate of 1:17.5 for the 1226G (N370S) mutation among Ashkenazi Jews in whom there is a predilection. Since clinical and radiological findings of avascular hip necrosis due to either Gaucher disease or LCPD may be indistinguishable, misdiagnosis may occur. The purpose of this study was to evaluate the incidence of 1226G Gaucher mutation in a cohort of radiologically confirmed LCPD patients (diagnosed 1986-2000) in Israel. Enzyme assay was performed for confirmation of affected versus carrier status in patients with the 1226G mutation. In all, 78 LCPD patients, 86% males, 51% with severe bone disease, were studied. Family history was negative for Gaucher disease. Ethnic origin was 39% Ashkenazi Jewish, 6% Arab, and 55% other ethnicities. One Ashkenazi Jewish LCPD patient was homozygous for the 1226G mutation, and 4 LCPD patients were carriers: 3 Ashkenazi Jewish and 1 Arab patient. The frequency of the 1226G mutation among the LCPD patients was increased relative to historical Ashkenazi Jewish Israeli controls (P = 0.01). Since Gaucher disease may be misdiagnosed as LCPD, glucocerebrosidase enzyme testing is recommended among Ashkenazi Jewish children diagnosed with LCPD.
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Leah Leibovitch, Gili Kenet, Kineret Mazor, Ilan Matok, Amir Vardi, Zohar Barzilay, Gideon Paret (2003)  Recombinant activated factor VII for life-threatening pulmonary hemorrhage after pediatric cardiac surgery.   Pediatr Crit Care Med 4: 4. 444-446 Oct  
Abstract: OBJECTIVE: To report intractable life-threatening pulmonary hemorrhage after cardiac surgery in an infant who was treated successfully with recombinant activated factor VII (rFVIIa). DESIGN: Descriptive case report. SETTING: An 18-bed pediatric intensive care unit at a tertiary-care children's hospital. Patient: A 10-wk-old child with acute life-threatening pulmonary hemorrhage after cardiac surgery. INTERVENTIONS: General supportive intensive care. MEASUREMENTS AND MAIN RESULTS: Care included mechanical ventilatory support, inotropic support, and concurrent treatment with blood products (packed cells, platelet concentrates, and plasma-derived products), as well as aprotinin and desmopressin to improve hemostasis. The addition of rFVIIa resulted in complete resolution of the hemorrhage. CONCLUSIONS: rFVIIa should be considered as a possible novel therapeutic approach to be used as rescue therapy for patients presenting with massive life-threatening hemorrhage progressing into hemorrhagic shock. Further controlled trials to elucidate the safety of this treatment are warranted.
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Gili Kenet, Ayala Maayan-Metzger, Nurit Rosenberg, Ben-Ami Sela, Ram Mazkereth, Aviyah Ifrah, Jacob Kuint (2003)  Thrombophilia does not increase risk for neonatal complications in preterm infants.   Thromb Haemost 90: 5. 823-828 Nov  
Abstract: The association between thrombophilia and neonatal complications was evaluated in a single-center prospective study. Prevalence of genetic prothrombotic markers (FVL, MTHFR, FIIG20210A) and levels of plasma homocysteine were assayed in 166 premature (mean gestational age: 30.9+/-2.3 weeks) and low birth weight (mean weight: 1327+/-319 grams) infants. The incidence of any neonatal complications was compared in infants with and without thrombophilia. A total of 38 infants were defined as "thrombophilic" due to heterozygous FVL (n=4) and/or FIIG20210A (n=8, including one case of combination with FVL) or homozygous 677T MTHFR (n=22) or homocysteine plasma levels above 15 micro mole/liter. Neonatal complications included: small for gestational age (28.8%), respiratory distress syndrome (51.8%), broncho-pulmonary dysplasia (10.2%), patent ductus arteriosus (12.7%), intraventricular hemorrhage (17%), periventricular leucomalacia (8.4%), retinopathy of prematurity (15.1%) and necrotizing enterocolitis in 1.2% of infants. No thrombosis was documented. The prevalence of perinatal complications and the severity of diseases were similar among infants with or without thrombophilia (p = 0.564). Our data suggest that preterm infants with thrombophilia are not at increased risk for developing neonatal complications.
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2002
 
PMID 
Arie Levine, Gabriel Kenet, Rafael Bruck, Yona Avni, Ilana Avinoach, Hussein Aeed, Zipporah Matas, Magda David, Avner Yayon (2002)  Effect of heparin on tissue binding activity of fibroblast growth factor and heparin-binding epidermal growth factor in experimental colitis in rats.   Pediatr Res 51: 5. 635-640 May  
Abstract: There have been several reports implying a benefit for heparin therapy in patients with refractory ulcerative colitis. Although this effect has been attributed to the anti-inflammatory properties of heparin, other mechanisms have not been excluded. Heparin is a potent modulator of receptor binding of growth factors such as fibroblast growth factor (FGF), vascular endothelial growth factor, and heparin-binding epidermal growth factor (HB-EGF), that play a role in wound repair. We examined the effect of heparin on the functional levels of FGF and HB-EGF in a model of experimental colitis. Fifty-six Wistar rats were divided into four groups: group 1 was the control group, group 2 received s.c. heparin 50 units/kg/d, group 3 underwent induction of 3% iodoacetamide colitis, and group 4 underwent induction of colitis and heparin treatment. Rats were killed and evaluated for severity of colitis by macroscopic and microscopic colitis scores, area of inflammation, and myeloperoxidase levels. FGF and HB-EGF levels were functionally assessed in colonic tissue in each group. Heparin therapy resulted in significant improvement in macroscopic and microscopic features of colitis (p < 0.05), accompanied by a partial reduction in myeloperoxidase levels. FGF receptor binding activity was identical in groups 1 and 2 but increased more than 3-fold after colitis induction in group 3 (p < 0.05). Treatment with heparin caused a significant decrease in FGF concentration. Levels of HB-EGF binding activity were similar in groups 1 and 2 and decreased in group 3 (p < 0.01). Heparin caused a significant increase in HB-EGF content in group 4 (p < 0.05). Levels of growth factors are altered differently in experimental colitis. Colonic FGF binding activity increases with colitis, whereas HB-EGF binding decreases with colitis. These trends were reversed by heparin, concomitant with a clinical and pathologic improvement in colitis. We suggest that one mechanism of heparin-mediated improvement in colitis may involve tissue healing associated with changes in functional levels of colonic growth factors.
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PMID 
G Goldstein, G Kenet (2002)  The impact of chronic disease on the family.   Haemophilia 8: 3. 461-465 May  
Abstract: Haemophilia is a chronic disease, affecting patients and their families. The impact of such a disease upon each family is dependent upon family type and characteristics and adjustment to it varies with time, in concordance with the family's lifecycle. In the National Hemophilia Center in Israel we lead a special support system and conduct group therapy from the very early stage of haemophilia diagnosis throughout the lifetime of patients. The general definitions of a family's lifecycle, the effect of the disease and the required adjustment to it are described in this paper. We refer to special difficulties associated with haemophilia as a chronic, genetic disease and describe ways to cope, discussing the support systems that have been established in our centre.
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Uri Martinowitz, Gili Kenet, Aharon Lubetski, Jacob Luboshitz, Eran Segal (2002)  Possible role of recombinant activated factor VII (rFVIIa) in the control of hemorrhage associated with massive trauma.   Can J Anaesth 49: 10. S15-S20 Dec  
Abstract: PURPOSE: To report our experience with recombinant activated factor VII (rFVIIa) to control hemorrhage in trauma patients with profound multifactorial coagulopathy. rFVIIa forms a complex with tissue factor exposed at sites of tissue damage and induces activation of coagulation limited to the site of injury. It is approved for use in hemophilia patients, however, its use in trauma is still controversial due to the theoretical risk of thromboembolic complications. CLINICAL FEATURES: Nineteen critically ill, multi-transfused patents with trauma (ten blunt and nine penetrating), aged 25 + 17 yr,were treated with rFVIIa after all conventional hemostatic measures had failed. After one to three doses of rFVIIa, hemorrhaging ceased within minutes in 15/19 (78.9%) patients. The total dose of rFVIIa required to control bleeding was 195 +/- 112.7 microg x kg(-1). Shortening of prothrombin time and partial thromboplastin time was observed within 15-30 min from 22.7 +/- 7.9 to 10.4 +/- 2.6 sec and 71 +/- 38.9 to 42.2 +/- 24 sec respectively, (P < 0.05). Transfusion requirements decreased from 30 +/- 18.3 units used within 5.6 +/- 3.4 hr of admission to 2.8 +/- 2.5 within the following 24 hr (P < 0.05). One patient developed clinical deep vein thrombosis. No systemic activation of coagulation was observed clinically. Thirteen patients (68.4%) survived and recovered. Four patents did not respond to rFVIIa treatment and exsanguinated within 24 hr. Two patients died after one week, one from sepsis and one from multi-organ failure. CONCLUSIONS: rFVIIa is a promising adjunctive hemostatic treatment for trauma patients suffering from massive bleeding. Controlled trials are warranted to evaluate the safety and efficacy of this drug.
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A Lubetsky, U Martinowitz, J Luboshitz, G Kenet, N Keller, I Tamarin, A Inbal (2002)  Efficacy and safety of a factor VIII-von Willebrand factor concentrate 8Y: stability, bacteriological safety, pharmacokinetic analysis and clinical experience.   Haemophilia 8: 5. 622-628 Sep  
Abstract: The present study was undertaken to evaluate stability, pharmacokinetic profile and efficacy of continuous infusion of 8Y in patients with different types of von Willebrand disease (vWD). Following reconstitution, 8Y levels of von Willebrand factor ristocetin cofactor (vWF:Rco), vWF antigen and factor VIII coagulant activity (FVIII:C) decreased to about 80% of the baseline levels; addition of low molecular weight heparin decreased the level of FVIII:C even further. Reconstituted 8Y was found to be sterile for up to 6 days postreconstitution. Ten vWD patients (four with type 2A, three with type 3, two with type 1 and one with 2N) underwent pharmacokinetic analysis. The recovery of vWF: RCo was significantly lower in patients with type 3 vWD (1.4 +/- 0.05% U(-1) kg(-1)) compared with that of the patients with types 1 (2.3 +/- 0.52% U(-1) kg(-1)) or 2A (2.0 +/- 0.06% U(-1) kg(-1)) vWD (P = 0.015). Type 3 vWD patients exhibited significantly higher vWF:RCo clearance (5.1 +/- 1.1 mL kg(-1) h(-1)) compared with that of patients with type 2A (2.8 +/- 0.7 mL kg(-1) h(-1)) and type 1 (2.6 +/- 1.0 mL kg(-1) h(-1)) vWD (P = 0.028). Accordingly, terminal half-life was lower in patients with type 3 vWD (8.0 +/- 0.6 h(-1)) compared with type 2A (12.7 +/- 5.9 h(-1)) or type 1 (14 +/- 1.2 h(-1)) vWD patients. Multimeric pattern of vWF from patients' plasma was similar to that of 8Y. In two patients treated with 8Y by continuous infusion for prevention or treatment of bleeding haemostasis was achieved. Thus, 8Y is suitable and haemostatically effective for continuous infusion treatment in patients with vWD.
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2001
 
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PMID 
N Sharon, Y Neumann, G Kenet, J Schachter, G Rechavi, A Toren (2001)  Successful pregnancy after high-dose cyclophosphamide and ifosfamide treatment in two postpubertal women.   Pediatr Hematol Oncol 18: 4. 247-252 Jun  
Abstract: Alkylating agents, especially cyclophosphamide, are known to have a destructive effect on the ovaries and to result in sterility in many young women treated with these drugs. This is especially true when the treatment is given to postpubertal women. The authors describe 2 postpubertal women aged 16 and 25 suffering from Ewing sarcoma who were treated with the very aggressive Sloan-Kettering protocol, which includes high-dose cyclophosphamide and ifosfamide in addition to other drugs. Both women had spontaneous pregnancies and delivered normal babies. The significance of these cases in view of the experimental various reproductive preservation measures offered to such women is discussed.
Notes:
 
PMID 
G Kenet, J Wardi, Y Avni, H Aeed, H Shirin, L Zaidel, R Hershkoviz, R Bruck (2001)  Amelioration of experimental colitis by thalidomide.   Isr Med Assoc J 3: 9. 644-648 Sep  
Abstract: BACKGROUND: Rectal administration of iodoacetamide induces colitis by blocking sulphhydryl groups and generating inflammatory mediators. Thalidomide, a non-barbiturate hypnotic, also has an anti-inflammatory effect, presumably by suppressing the production of tumor necrosis factor alpha. In patients with Crohn's disease, neutralization or suppression of TNF alpha reduces inflammation. OBJECTIVES: To evaluate the effects of thalidomide in a model of experimental colitis. METHODS: Colitis was induced in rats by intracolonic administration of 3% iodoacetamide. In the treatment group, thalidomide 50 mg/kg was given daily by gavage and continued for 7 days until the rats were sacrificed. Their colons were then processed for wet weight, lesion area, weight of mucosal scraping, myeloperoxidase activity and histology. Serum levels of TNF were determined. RESULTS: Colonic wet weight, lesion area, myeloperoxidase activity and serum levels of TNF alpha were significantly lower (P < 0.05) in the treatment group (iodoacetamide + thalidomide) than the control group (iodoacetamide only). Histologically, colonic inflammation in the treated group was markedly decreased. CONCLUSIONS: Thalidomide effectively decreases colitis induced by iodoacetamide. The mechanism is probably associated with inhibition of TNF alpha, and should be further studied.
Notes:
 
PMID 
U Martinowitz, G Kenet, E Segal, J Luboshitz, A Lubetsky, J Ingerslev, M Lynn (2001)  Recombinant activated factor VII for adjunctive hemorrhage control in trauma.   J Trauma 51: 3. 431-8; discussion 438-9 Sep  
Abstract: BACKGROUND: Recombinant activated factor VII (rFVIIa) was approved for treatment of hemorrhages in patients with hemophilia who develop inhibitors to factors VIII or IX. Conditions with increased thromboembolic risk, including trauma with or without disseminated intravascular coagulation, were considered a contraindication for the drug. The mechanism of action of rFVIIa suggests enhancement of hemostasis limited to the site of injury without systemic activation of the coagulation cascade. Therefore, use of the drug in trauma patients suffering uncontrolled hemorrhage appears to be rational. METHODS: Seven massively bleeding, multitransfused (median, 40 units [range, 25-49 units] of packed cells), coagulopathic trauma patients were treated with rFVIIa (median, 120 microg/kg [range, 120-212 microg/kg]) after failure of conventional measures to achieve hemostasis. RESULTS: Administration of rFVIIa resulted in cessation of the diffuse bleed, with significant decrease of blood requirements to 2 units (range, 1-2 units) of packed cells (p < 0.05); shortening of prothrombin time and activated partial thromboplastin time from 24 seconds (range, 20-31.8 seconds) to 10.1 seconds (range, 8-12 seconds) (p < 0.005) and 79 seconds (range, 46-110 seconds) to 41 seconds (range, 28-46 seconds) (p < 0.05), respectively; and an increase of FVII level from 0.7 IU/mL (range, 0.7-0.92 IU/mL) to 23.7 IU/mL (range, 18-44 IU/mL) (p < 0.05). Three of the seven patients died of reasons other than bleeding or thromboembolism. CONCLUSION: The results of this report suggest that in trauma patients rFVIIa may play a role as an adjunctive hemostatic measure, in addition to surgical hemostatic techniques, and provides the motivation for controlled animal and clinical trials.
Notes:
2000
 
PMID 
G Kenet, S Sadetzki, H Murad, U Martinowitz, N Rosenberg, S Gitel, G Rechavi, A Inbal (2000)  Factor V Leiden and antiphospholipid antibodies are significant risk factors for ischemic stroke in children.   Stroke 31: 6. 1283-1288 Jun  
Abstract: BACKGROUND AND PURPOSE: The association between ischemic childhood stroke and thrombophilia has been debated. We studied the prevalence of thrombophilia risk factors in 65 unrelated children with ischemic stroke compared with 145 control subjects. METHODS: Patients and control subjects were tested for antithrombin protein C and protein S deficiencies, the presence of antiphospholipid antibodies (APLA), factor V Leiden (FVL), G20210A polymorphism of factor II gene (FII G20210A), and C677T polymorphism of 5,10-methylenetetrahydrofolate reductase gene (C677T MTHFR). RESULTS: Of 65 children, 7 had a stroke in the neonatal/perinatal period and therefore were analyzed separately. Thirty-one of the remaining 58 patients with pediatric stroke (53.4%) were found to have at least 1 thrombophilia marker compared with only 25.5% of control subjects. None of the patients or control subjects had protein S or antithrombin III deficiency. The prevalence of protein C deficiency was higher among pediatric stroke patients than among control subjects, but the difference was not statistically significant (OR=7, 95% CI 0.75 to 65.1). Heterozygous FII G20210A and homozygous MTHFR 677T were not associated with an increased risk for stroke (OR=1.29, 95% CI 0.2 to 8.2; and OR=1.06, 95% CI 0.4 to 2.7, respectively). In contrast, the presence of APLA was associated with a >6-fold risk of stroke (OR=6. 08, 95% CI 1.5 to 24.3), and the heterozygosity for FVL increased the risk of stroke by almost 5-fold (OR=4.82, 95% CI 1.4 to 16.5). Five patients with pediatric stroke had a combination of > or =2 thrombophilia markers, whereas none of the control subjects had a combination of the markers. Most of the patients with neonatal/perinatal stroke were found to have at least 1 thrombophilia marker. CONCLUSIONS: These data suggest that the prevalence of thrombophilia markers is increased in children with stroke compared with control subjects and, specifically, that FVL and APLA contribute significantly to stroke occurrence.
Notes:
 
PMID 
G Kenet, A Lubetsky, S Gitel, J Luboshitz, D Varon, U Martinowitz (2000)  Treatment of bleeding episodes in patients with hemophilia and an inhibitor: comparison of two treatment protocols with recombinant activated factor VII.   Blood Coagul Fibrinolysis 11 Suppl 1: S35-S38 Apr  
Abstract: Six hemophilia A patients with inhibitors were treated with a continuous infusion of recombinant activated factor VII (rFVIIa) for various bleeding episodes. Bleeding episodes (n = 101) were treated according to a 12 h regular dose protocol or a shortened (6 h) augmented dose protocol. Patient response to therapy was assessed by symptomatic improvement within predefined timeframes. Although patient number was limited, both protocols appeared similar with respect to the proportion of patients responding to therapy; however, the augmented dose protocol appeared to be superior to the regular dose protocol with shorter response time, shorter duration of therapy and possibly lower rFVIIa requirements. Further studies are needed to define the efficacy of rFVIIa augmented dose administered as continuous infusion in treating hemophilia patients with inhibitors during major bleeding episodes, trauma and surgery.
Notes:
1999
 
DOI   
PMID 
G Kenet, R Walden, A Eldad, U Martinowitz (1999)  Treatment of traumatic bleeding with recombinant factor VIIa.   Lancet 354: 9193. Nov  
Abstract: Surgical intervention failed to stop life-threatening bleeding caused by injury complicated by severe coagulopathy. Administration of recombinant factor VIIa immediately corrected the coagulopathy and bleeding stopped.
Notes:
 
PMID 
A Lubetsky, S Schulman, D Varon, U Martinowitz, G Kenet, S Gitel, A Inbal (1999)  Safety and efficacy of continuous infusion of a combined factor VIII-von Willebrand factor (vWF) concentrate (Haemate-P) in patients with von Willebrand disease.   Thromb Haemost 81: 2. 229-233 Feb  
Abstract: We studied the safety and efficacy of treatment with continuous infusion of a von Willebrand factor (vWF) concentrate Haemate-P in patients with von Willebrand disease (vWD). Three patients with mild and 5 patients with severe forms of vWD, were treated with continuous infusion of Haemate-P by minipump. The indications for treatment were: to prevent bleeding during 9 surgical procedures or 1 vaginal delivery in 6 patients and to treat 2 bleeding episodes in 2 patients. The patients were monitored daily for factor VIII (FVIII:C) and ristocetin cofactor (vWF: RCo) levels and the infusion rate was adjusted to maintain the desired therapeutic level of vWF:RCo. The treatment was effective in preventing surgical bleeding and controlling bleeding episodes. All factor VIII:C and most of the vWF:RCo levels measured during the study period were above the target therapeutic levels. A significant decrease in clearance of FVIII:C and vWF:RCo was observed over the treatment period. Haemate-P consumption averaged 24.3+/-7.9 vWF:RCo U/kg/day which is approximately half the expected dose had intermittent bolus injections been used. We suggest that continuous Haemate-P infusion is superior to intermittent bolus injections for the treatment of vWD patients by virtue of its efficiency, simplicity and considerable savings.
Notes:
 
PMID 
G Kenet, J Freedman, B Shenkman, E Regina, F Brok-Simoni, F Holzman, F Vavva, N Brand, A Michelson, M Trolliet, J Loscalzo, A Inbal (1999)  Plasma glutathione peroxidase deficiency and platelet insensitivity to nitric oxide in children with familial stroke.   Arterioscler Thromb Vasc Biol 19: 8. 2017-2023 Aug  
Abstract: In a previous report by Freedman et al (J Clin Invest. 1996;97:979-987), plasma from 2 brothers with stroke or transient ischemic attack inactivated the antiplatelet effects of nitric oxide (NO), and this effect was found to be a consequence of a deficiency of plasma glutathione peroxidase (GSH-Px). In this study, we attempted to define the generalizability of this deficiency by studying NO-mediated antiplatelet effects in 7 families with familial childhood stroke. Seven families with familial childhood stroke that consecutively presented to a large referral center were included in the study. We monitored ADP-induced aggregation of normal gel-filtered platelets (GFP) in platelet-poor plasma (PPP) from normal individuals and from patients in the presence or absence of an NO donor (S-nitroso-glutathione). Surface P-selectin expression of normal GFP in patients' PPP was analyzed by flow cytometry after incubation with a P-selectin-specific monoclonal antibody in the presence or absence of the NO donor. We also measured GSH-Px activity in plasmas from family members and normal controls using standard methods. In 6 of 7 families, NO failed to inhibit platelet P-selectin expression and platelet aggregation in PPP from the affected family members and some of their relatives. Of 4 families studied, 3 probands and their corresponding affected parent had 50% decrease in plasma GSH-Px activity. In some patients with childhood stroke, impaired metabolism of reactive oxygen species as a result of reduced GSH-Px activity results in NO insufficiency that affects normal platelet inhibitory mechanisms and predisposes to arterial thrombosis.
Notes:
 
PMID 
S Hayek, G Kenet, A Lubetsky, N Rosenberg, S Gitel, S Wientroub (1999)  Does thrombophilia play an aetiological role in Legg-Calvé-Perthes disease?   J Bone Joint Surg Br 81: 4. 686-690 Jul  
Abstract: Heritable thrombophilic disorders have been proposed as one of the causes for Legg-Calvé-Perthes disease. A total of 62 patients diagnosed with this disease between 1988 and 1997 and 50 controls were screened for thrombophilia. The incidence and relationship of thrombophilia to the severity of the disease were evaluated. One patient and none of the controls had protein S deficiency. One of the control group and one of the patients had protein C deficiency with the latter child also having a combined deficiency with a mutant factor V gene. The number of children with a mutant factor V gene, protein C deficiency, who were homozygous for the C 677T polymorphism of methylenetetrahydrofolate reductase or were heterozygous for mutant G20210A prothrombin did not differ statistically in the study and the control groups. No patient had antithrombin deficiency or positive lupus anticoagulant. We found no correlation between thrombophilia and the extent of the disease. The most common risk factors for arteriovenous thromboembolism showed no statistical significance in our patients compared with the control group or with the general population. These data do not confirm an aetiological role for thrombophilia in Perthes' disease.
Notes:
1998
 
PMID 
G Kenet, N Sharon, E Rosner, A Toren, Y Neumann, M Mandel, C Kaplinsky, N Gipsh, S Berman, G Rechavi (1998)  Chromosomal translocation (1:13) in a case of alveolar rhabdomyosarcoma.   J Pediatr Hematol Oncol 20: 1. 86-87 Jan/Feb  
Abstract: PURPOSE: To describe a patient with a variant translocation (1;13)(p36;q14) in an alveolar rhabdomyosarcoma and compare the clinical course with four other cases. PATIENTS AND METHODS: A 10-year-old girl presented with multiple masses involving the thigh, abdomen, chest wall, and scalp with pleural effusion and edema of the lower extremities. RESULTS: A bone marrow biopsy, aspirate, and biopsy of the thigh mass all showed tumor invasion. Histopathology and cytogenetics of the thigh mass revealed an alveolar rhabdomyosarcoma with a t(1;13)(p36q14) variant. There was no response to aggressive therapy and the patient died within 3 weeks of admission. CONCLUSION: Variant t(1;13)(p36;q14) has now been described in 5 cases of rhabdomyosarcoma, and may define a subset of patients with extensive disease at diagnosis unresponsive to current therapeutic modalities.
Notes:
 
PMID 
C Kaplinsky, G Kenet, U Seligsohn, G Rechavi (1998)  Association between hyperflexibility of the thumb and an unexplained bleeding tendency: is it a rule of thumb?   Br J Haematol 101: 2. 260-263 May  
Abstract: A bleeding tendency manifested by petechiae and ecchymoses is one of the most common causes for referral of patients to haematology clinics. Vessel wall pathology is not usually considered to be a cause for deranged haemostasis, although coexistence of increased capillary fragility and joint hypermobility have been reported. We determined the frequency of thumb hyperextensibility and scored the findings in a series of 44 patients referred because of ecchymoses and petechiae, as well as 261 control children and their mothers. All 44 patients had normal coagulation studies. Thumb flexibility score was +4 in 30 patients, +3 in eight patients, +2 in five patients and +1 in one of the index patients. In the control group, only one of 261 had a +4, and three had a +3 score, and two of 260 mothers had a +4 score. Ecchymoses were not observed in any of these subjects, nor in the +1 patients. Based on clinical presentation and normal coagulation studies, we suggest that our patients had an underlying subtype of Ehlers-Danlos syndrome. In view of the dramatically high occurrence of thumb hyperextensibility in patients with unexplained mild bleeding tendency, costly haemostatic and coagulation studies on such patients may not be necessary.
Notes:
 
PMID 
G Kenet, A Lubetsky, B Shenkman, I Tamarin, R Dardik, G Rechavi, A Barzilai, U Martinowitz, N Savion, D Varon (1998)  Cone and platelet analyser (CPA): a new test for the prediction of bleeding among thrombocytopenic patients.   Br J Haematol 101: 2. 255-259 May  
Abstract: The risk of bleeding among thrombocytopenic patients was evaluated using our new cone and platelet analyser (CPA) test. Using this test, adherence of platelets was quantitated on extracellular matrix and expressed as percent of surface coverage (SC) and the average size (AS) of aggregates. 42 thrombocytopenic patients with ITP (n=23), post chemotherapy (n= 12) and others (n= 7) were tested over a total of 82 visits. On each visit, complete blood count and CPA tests were performed and patients were evaluated for evidence of bleeding (found in 40 visits). Bleeding patients had significantly lower platelet counts (27.4 +/- 22.0 v 47.1 +/- 21.0 x 10(9)/l), lower haematocrit values (30.2 +/- 8.1 v 35.2 +/- 6.6%), lower MPV (6.83 +/-1.89 v 8.98 +/- 1.13 fl), and lower SC (4.87 +/- 3.95 v 10.33 +/-5.48%) and AS (33.99 +/- 14.94 v 52.9 +/- 24.34 microm2). Univariate analysis yielded platelet count < or =20.0 x 10(9)/l, MPV < or =8 fl, haematocrit <35%, SC <5%, AS< or =40 microm2 as significantly associated with bleeding, whereas only MPV and SC were associated with bleeding (OR 6.95, CI 2.25-21.46 and OR 4.27, CI 1.29-14.16, respectively) by multivariate analysis. When taken together, 21/22 of patients (95%) with both low SC (<5%) and low MPV (<8.0 fl) had bleeding symptoms, whereas only 9/43 (21%) patients with both these parameters above these values experienced bleeding symptoms. We conclude that the CPA test and the parameter SC (<5%) together with MPV (< or =8 fl) might be used as independent predictors of bleeding in the management of thrombocytopenic patients.
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1997
 
PMID 
C Kaplinsky, A Toren, Y Neumann, M Mandel, G Kenet, N Sharon, G Rechavi, M Biniaminov, V Rubanov, E Rosenthal, E Rosner, Z Mark, N Amariglio, F Brok-Simoni (1997)  Central nervous system involvement at diagnosis in a case of pediatric CD30+ anaplastic large cell lymphoma.   Med Pediatr Oncol 28: 2. 132-135 Feb  
Abstract: Central nervous system (CNS) involvement in Ki-1/CD30 lymphoma is extremely rare, in contrast to the frequent involvement in other types of pediatric non-Hodgkin's lymphoma. No mechanism has yet been proposed to explain the sparing of the blood brain barrier in Ki-1/lymphoma. We present a 2-year-old boy who was admitted to the Department of Pediatric Hemato-Oncology due to lethargy, progressive breathing difficulties, massive diffuse lymphadenopathy, hepatosplenomegaly, and ichthyosis-like skin involvement with epidermolysis. A lymph node biopsy was compatible with Ki-1/CD30 anaplastic large cell lymphoma (ALCL). Bone marrow aspirate and biopsy demonstrated reactive hyperplasia. Cytogenetic analysis displayed hyperdiploid cells with 1p(-) in most cells. Cerebrospinal fluid examination showed pleocytosis with CD30+ cells. Possible mechanisms which could enable CNS involvement in this unusual case are discussed.
Notes:
 
PMID 
A Inbal, G Kenet, A Zivelin, T Yermiyahu, T Bronstein, T Sheinfeld, H Tamari, S Gitel, G Eshel, J Duchemin, M Aiach, U Seligsohn (1997)  Purpura fulminans induced by disseminated intravascular coagulation following infection in 2 unrelated children with double heterozygosity for factor V Leiden and protein S deficiency.   Thromb Haemost 77: 6. 1086-1089 Jun  
Abstract: Purpura fulminans is associated with homozygous protein C and homozygous protein S deficiency or may follow bacterial or viral infections. We present 2 children from 2 unrelated Arab families with purpura fulminans who were double heterozygotes for factor V Leiden inherited from their fathers and protein S deficiency inherited from their mothers. No previous thrombotic events have occurred in either patient or their respective family members. In one patient sepsis accompanied by disseminated intravascular coagulation appeared to be the trigger of purpura fulminans. In the other patient varicella infection preceded purpura fulminans and was also associated with disseminated intravascular coagulation. This report emphasizes the need for evaluation of hereditary defects in the inhibitory mechanisms of blood coagulation in patients with purpura fulminans at any age.
Notes:
 
PMID 
N Sharon, G Kenet, A Toren, M Mandel, Y Neumann, C Kaplinsky, G Schiby, G Rechavi (1997)  Helicobacter pylori-associated gastric lymphoma in a girl.   Pediatr Hematol Oncol 14: 2. 177-180 Mar/Apr  
Abstract: We present a case of a 14-year-old girl with gastric large cell lymphoma. The girl's lymphoma was characterized by the presence of mucosa-associated lymphoid tissue. Infection with Helicobacter pylori (HP) was ascertained at the time of diagnosis. The girl was successfully treated by a combination of chemotherapy (MACOP-B) and anti-HP drugs (omeprazole plus amoxicillin). Thrombus of the inferior vena cava, a rare complication, evolved during treatment.
Notes:
1996
 
DOI   
PMID 
Y Neumann, A Toren, G Rechavi, B Seifried, N G Shoham, M Mandel, G Kenet, N Sharon, M Sadeh, R Navon (1996)  Vincristine treatment triggering the expression of asymptomatic Charcot-Marie-Tooth disease.   Med Pediatr Oncol 26: 4. 280-283 Apr  
Abstract: A 16-year-old male suffering from Ewing's sarcoma of the pelvis was treated with vincristine as part of his chemotherapeutic protocol. The boy was never known to suffer from any neurological problems. His father had a mild limp, attributed to prolonged "taxi driving," that was never investigated medically. The first course of treatment, which included 2 mg of vincristine, resulted in clinical improvement. However, at the same time the patient developed severe weakness of both upper and lower limbs, areflexia, and gradually a pes cavus deformity. Nerve conduction studies were suggestive of severe peripheral sensorimotor neuropathy, axonal and demyelinative. A definite diagnosis of Charcot-Marie-Tooth was confirmed by molecular analysis showing the typical duplication of 1.5 megabases at 17 p11.2. This unique manifestation of vincristine neurotoxicity is reported and discussed.
Notes:
1995
 
PMID 
G Kenet, M Mandel, Y Mor, A Toren, P Jonas, G Kende, G Rechavi, Y Neumann (1995)  Genetic predisposition and cyclophosphamide treatment in a girl with bladder carcinoma?   Med Pediatr Oncol 24: 4. 269-270 Apr  
Abstract: Transitional cell carcinoma of the bladder rarely occurs in young female patients. We present a case of bladder carcinoma which appeared after treatment with cyclophosphamide, in a 14-year-old girl genetically predisposed to bladder cancer.
Notes:
 
PMID 
A Ballin, E Arbel, G Kenet, M Berar, D Kohelet, A Tanay, H Zakut, D Meytes (1995)  Autologous umbilical cord blood transfusion.   Arch Dis Child Fetal Neonatal Ed 73: 3. F181-F183 Nov  
Abstract: The purpose of this study was to examine some aspects of umbilical cord blood collection for autologous transfusion in premature infants. All 120 microbacterial cultures (aerobic and anaerobic) of cord blood samples as well as 30 cultures of mycoplasma were treated. Cord prothrombin fragment (F 1 + 2) concentrations were quantified at one and 10 minutes after clamping of the cord. F 1 + 2 concentrations assessed on 25 newborn infants were similar and no linear association with time of clamping could be drawn. This means that cord blood thrombosis is not activated for at least 10 minutes following clamping of the cord. As far as is known, the first newborn infant to benefit from this method of transfusion is reported here. The premature infant received two portions of autologous blood (on days 5 and 7). No untoward effects were noted. Blood, collected from the umbilical cord, is a safe source for autotransfusion, provided that bacteriological testing has been carried out.
Notes:
 
PMID 
A Toren, N Sharon, M Mandel, Y Neumann, G Kenet, C Kaplinsky, J Dor, G Rechavi (1995)  Two embryonal cancers after in vitro fertilization.   Cancer 76: 11. 2372-2374 Dec  
Abstract: BACKGROUND. In vitro fertilization is not considered to be associated with an increased rate of pediatric malignancies, and only three have been reported in the literature. Two additional rare pediatric tumors in children conceived through this technique are reported. METHODS. Two children 12 and 18 months of age, developed hepatoblastoma and clear cell sarcoma of the kidney, respectively. They were both products of uneventful pregnancies induced by in vitro fertilization. No other environmental, prenatal, or family factor was found. RESULTS. The first child died after a failed remission induction with cisplatin, doxorubicin, and vincristine, whereas the second child is alive with no evidence of disease 18 months after diagnosis and treatment according to NWTS protocol. CONCLUSIONS. A possible association between in vitro fertilization and pediatric malignancies is suggested.
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1994
 
PMID 
G Kende, A Toren, M Mandel, Y Neumann, G Kenet, F Brok-Simoni, B Ramot, I Ben-Bassat, G Rechavi (1994)  Familial leukemia: description of two kindreds and a review of the genetic aspects of the disease.   Acta Haematol 92: 4. 208-211  
Abstract: We describe two kindreds of Arab ancestry characterized by multiple cases of acute lymphoblastic leukemia. Consanguinity and intermarriages were prevalent in the two families. Age, mode of presentation, characteristics of the leukemic cells, response to treatment and prognosis were remarkably similar among the patients. A short review of the literature on familial leukemia is given.
Notes:
 
PMID 
G Kenet, F Salomon, Z Samra, J Pinkhas, Y Sidi, N Arber (1994)  Fatal Shigella sepsis in a neutropenic patient.   Mt Sinai J Med 61: 4. 367-368 Sep  
Abstract: Bacteremia during infection with Shigella is relatively rare and usually self-limited. Bacteremia during shigellosis bearing a high fatality rate has been reported in young infants and in persons with malnutrition or with the acquired immunodeficiency syndrome. We report a case of Shigella sonnei septicemia in a severely neutropenic patient who had fever, abdominal pain, diarrhea, malnutrition, and dehydration. She died after five days despite intensive care. We emphasize that Shigella should be considered among the possible pathogens causing sepsis in neutropenic patients.
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PMID 
M Mandel, A Toren, G Kende, Y Neuman, G Kenet, G Rechavi (1994)  Familial clustering of malignant germ cell tumors and Langerhans' histiocytosis.   Cancer 73: 7. 1980-1983 Apr  
Abstract: Three sisters in a family with seven children whose grandmother had an ovarian embryonal carcinoma experienced development of malignant and a malignant-like situation in childhood. Two were diagnosed as having malignant germ cell tumors of the ovary, and the third was found to have Langerhans' histiocytosis. The two girls with germ cell tumor shared an identical human leukocyte antigen, whereas the sister with histiocytosis shared one identical haplotype with them. All three children have been treated successfully with chemotherapy and are doing well off of treatment.
Notes:
 
PMID 
M Berkowicz, A Toren, E Rosner, M Mandel, A Vonsover, M Biniaminov, N Amariglio, Z Mark, G Kenet, Y Neumann (1994)  Lymphomatous T-cell leukemia in two Arab children. Is there a role for an environmental effect.   Leukemia 8: 11. 1995-1998 Nov  
Abstract: Two Arab children from the Gaza strip presented with fever, weakness, hepatosplenomegaly, lymphadenopathy and leukocytosis. The peripheral and bone marrow blasts had an immunophenotype compatable with T-cell acute lymphoblastic leukemia, and exhibited unusual markers (CD2+, CD3+, CD4-, CD8-). Cytogenetic studies revealed t(8;14)(q24;q11), possibly involving the alpha/delta locus of the T-cell receptor gene on chromosome 14 rather than the immunoglobulin heavy-chain locus usually involved in the t(8;14)(q24;q32), which is typical for Burkitt's leukemia/lymphoma. One of the children had a brother who died of T-cell acute lymphoblastic leukemia a few years later, however, his blasts showed deletion of chromosome 12. The possible role for environmental factors associated with low socioeconomic status, as well as of genetic factors in leukemogenesis are discussed.
Notes:
 
PMID 
A Ballin, G Kenet, R Gutman, Z Samra, H Zakut, D Meytes (1994)  Autologous cord blood transfusion.   Acta Paediatr 83: 7. 700-703 Jul  
Abstract: Newborn piglets were exsanguinated (60% of blood volume) and retransfused 1 h later. One test group received adult pig red blood cells, the other piglet cord blood cells; controls were infused with plasma. While all controls died, satisfactory results were achieved in piglets transfused with either adult or foetal blood. The feasibility of collecting human cord blood for transfusion was assessed in 100 samples of human cord blood. Blood was collected aseptically and aerobic and anaerobic cultures set up. All samples of cord blood were sterile, and all were Mycoplasma negative. Coagulation parameters were analysed in eight cord plasma samples stored at -20 degrees C for 45 days. No significant abnormalities were found immediately after birth or after storage.
Notes:
 
PMID 
A Toren, G Kende, M Mandel, M Biniaminov, F Brok-Simoni, E Rosenthal, I Engelberg, Y Neumann, G Kenet, I Ben-Bassat (1994)  In vivo clonal evolution of pre-B to B-cell acute lymphoblastic leukemia in childhood.   Leukemia 8: 6. 1062-1064 Jun  
Abstract: Two cases are described that provide further evidence for clonal evolution in pre-B-cell acute lymphoblastic leukemia. Two infants, whose lymphoblasts at diagnosis were morphologically subtyped as L1 and immunophenotyped as HLA DR+, CD19+, CD10+/- and C mu-, were induced and maintained in remission. One child relapsed 6 months after initiation of therapy. This time his lymphoblasts had L3 morphology and immunophenotyping demonstrated the appearance of surface immunoglobulins. The second child relapsed 18 months after initiation of therapy with a lymphomatous picture. He also had peripheral and bone marrow blasts with L3 morphology and surface immunoglobulins. A lymph node biopsy showed diffuse small non-cleaved lymphoma with a 'starry sky' appearance compatible with Burkitt's lymphoma. Only one case with a similar clonal evolution has been reported in the literature, but no surface immunoglobulins were demonstrated. The significance of clonal evolution in these cases and its potential practical implications are discussed.
Notes:
1993
 
PMID 
M Lishner, G Kenet, A Lalkin, S Yarkoni, H Ben-Bassat, M Fejgin, G Rechavi, A Amiel (1993)  Fluorescent in situ hybridization for the detection of t(8:14) in Burkitt's lymphoma.   Acta Haematol 90: 4. 186-189  
Abstract: Burkitt's lymphoma cells exhibit the reciprocal balanced chromosomal translocation t(8:14) in 75% of patients. Cytogenetic analysis is time-consuming, requires in vitro culture with mitogens and enables to analyse a relatively small number of cells. We evaluated the role of multicolor fluorescent in situ hybridization (FISH) in the rapid detection of t(8:14) in Burkitt's lymphoma cells. FISH detected the JH/myc translocation in 100% of the cells of five cell lines carrying the classical t(8:14) and in fresh cells obtained from a newly diagnosed Burkitt's lymphoma patient. In contrast, the translocation was not detected in the Bajb cell line that does not carry t(8:14). We conclude that FISH is a rapid and reliable diagnostic tool for the detection of the JH/myc translocation in Burkitt's lymphoma patients.
Notes:
1990
 
PMID 
A Ballin, G Kenet, H Tamary, G Rechavi, G Chividalli, Y Burstein, T Tauber, M Nussinovitch, D Meytes (1990)  Infantile idiopathic thrombocytopenic purpura.   Pediatr Hematol Oncol 7: 4. 323-328  
Abstract: Idiopathic thrombocytopenic purpura (ITP) in childhood is a benign disease, as only 10% to 20% of the patients have a chronic course. A retrospective study of 57 ITP patients ranging in age from four months to two years revealed that 30% of them proceeded to chronicity. Unlike ITP in the general pediatric population, chronic infantile ITP was characterized by male predominance, a high frequency of preceding viral infections, and lack of responsiveness to any of the known modalities of treatment.
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