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ABSTRACT: Prolonged thrombocytopenia complicated by bleeding episodes represent a major problem following autologous bone marrow transplantation (ABMT). Recombinant human interleukin-6 (rhIL-6) has been shown to be a maturation factor for both mouse and human megakaryocytes. We administered rhIL-6 to a 43 year old woman who developed marked resistant and prolonged thrombocytopenia with bleeding episodes following autologous peripheral blood stem cell transplantation (APBSCT). Twenty days after the initiation of rhIL-6 therapy, the number of megakaryocyte (MK) progenitors (CFU-MK and BFU-MK) cultured from the peripheral blood increased followed by a moderate increase in the number of bone marrow megakaryocytes. The platelet count increased and the bleeding episodes disappeared. Although spontaneous platelet recovery cannot be ruled out in this case it seems that rhIL-6 may be an important thrombopoietic factor for severe thrombocytopenia following APBSCT.
06/2009; 19(3-4):343-349.
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Annals of the New York Academy of Sciences 12/2006; 556(1):437 - 440. · 3.15 Impact Factor
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ABSTRACT: The capacity of cultured bovine aortic, capillary, and corneal endothelial cells as well as of human umbilical cord endothelial cells to produce interferon (IFN) was investigated. The endothelial cells of the two species produced significant amounts of IFN in response to various viruses and poly (I) poly (C). The IFN produced by human umbilical cord endothelial cells was a mixture of α- and β-IFN, as determined by neutralization with antibodies directed against these two types of IFNs as well as by measuring the antiviral activity on heterologous cells. Bovine endothelial cells also produced a mixture of at least two IFN subspecies, one of them labile at pH 2 and active on human cells and the other stable at pH 2 and inactive on human cells.
Journal of Cellular Physiology 02/2005; 122(2):200 - 204. · 3.87 Impact Factor
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ABSTRACT: Treatment with intensive chemotherapy regimens is frequently complicated by severe thrombocytopenia. During the period of severe thrombocytopenia, anticoagulant treatment is not uncommonly indicated for thromboembolic events or thromboprophylaxis in these patients. We report 10 hematological patients treated with intensive chemotherapy protocols that were anticoagulated with enoxaparin for catheter related central venous thrombosis and thromboprophylaxis. During the period of severe thrombocytopenia the dosages of enoxaparin were reduced and no major bleeding occurred. Based on our experience we suggest that reduced dosages of low molecular weight heparins may be used relatively safely during transient severe thrombocytopenia.
Leukemia and Lymphoma 08/2004; 45(7):1407-11. · 2.58 Impact Factor
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ABSTRACT: The general safety and efficacy of intravenous immunoglobulin (IGIV) as treatment for idiopathic thrombocytopenic purpura (ITP) has been well-studied. The current study compares the safety and efficacy of a novel IGIV (IGIV-C; Gamunex, 10%) with a licensed solvent/detergent-treated product (IGIV-S/D; GamimuneN, 10%) in treatment of ITP. Ninety-seven pediatric and adult patients with acute and chronic ITP were treated in a multi-center, prospective, randomized, double-blind parallel group, non-inferiority trial at 26 international sites. Baseline data (age, duration of ITP, platelet counts, previous treatment) were comparable between groups. Patients were treated with 1 g/kg/day of IGIV-C or IGIV-S/D for 2 days. The primary end-point, proportion of patients whose platelet counts increased from >/=20 x 10(9)/L to >/=50 x 10(9)/L within 7 days after dosing, was achieved by 35/39 (90%) and 35/42 (83%) of patients treated with IGIV-C and IGIV-S/D, respectively. A secondary endpoint, maintaining platelet counts >/=50 x 10(9)/L for >/=7 days, was achieved by 29/39 (74%) of IGIV-C and 25/42 (60%) IGIV-S/D treated patients. Compared with IGIV-S/D, fewer patients treated with IGIV-C received corticosteroids beyond day 7 (p = 0.02). Efficacy was independent of the presence of isoantibodies or blood type, supporting mechanisms of effect different from anti-D treatments. Adverse events were generally mild and occurred with similar frequency in each group. Viral safety monitoring for HIV, HCV, HBV and Parvovirus B19 showed no seroconversions on study. In conclusion, IGIV-C is as safe and efficacious as IGIV-S/D in treatment of ITP.
Thrombosis and Haemostasis 05/2004; 91(4):771-8. · 5.04 Impact Factor
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ABSTRACT: Background: Patients carrying variant CYP2C9 alleles are prone to bleeding complications under standard warfarin treatment. Our aim was to test the feasibility of warfarin therapy in patients with severe, inherited CYP2C9 deficiency. Methods: CYP2C9 genotypes and clinical characteristics were compared retrospectively in patients who maintain stable anticoagulation on low or regular doses of warfarin. Results: In the low-dose (10.5+/-2.9 mg/week) group (N=16), we identified six (37.6%) patients with severe CYP2C9 deficiency and three each with *2/*3 and *3/*3 genotypes as compared to none in the standard dose (39.2+/-17.9 mg/week) group (N=17). Warfarin dose (mg/week) was correlated with genotype in all patients as follows: *1/*1 (N=14) dose=33.6+/-19.4; *1/*2 (N=9) dose=30.4+/-21.6; *1/*3 (N=4) dose=15.3+/-10.7; *2/*3 (N=3) dose=10.6+/-3.6; *3/*3 (N=3) dose=7.3+/-3.1. Age and frequency of concurrent warfarin potentiating medication administration were higher in the low-dose group than in the standard dose group of patients. Conclusions: Warfarin treatment is feasible in individuals with severe, inherited CYP2C9 deficiency. Dose requirement was correlated with CYP2C9 genotype and possibly affected by age and concurrent intake of interfering drugs. Prospective studies are needed to test the feasibility and cost effectiveness of using algorithms based on these parameters for adjusting initial warfarin dose to meet individual needs.
European Journal of Internal Medicine 03/2004; 15(1):22-27. · 2.00 Impact Factor
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ABSTRACT: Bleeding is the most serious adverse event of oral anticoagulants and is a major cause of morbidity and mortality in such patients. Rapid reversal of anticoagulation in bleeding patients or prior to urgent surgery is mandatory. The therapeutic options in these situations include administration of fresh frozen plasma (FFP), and recently of prothrombin complex concentrates (PCCs). However, viral safety and thrombogenicity of PCCs remain issues of concern. In the present study, we administered Octaplex, a new solvent/detergent (S/D) treated and nanofiltered PCC, to excessively anticoagulated bleeding patients or to anticoagulated patients facing urgent surgery. Ten excessively anticoagulated patients with major bleeding and 10 anticoagulated patients awaiting surgery (median age 72.5 (43-83) years, 9 females) received a median dose of 26.1 IU/kg body weight (BW) of Octaplex for reversal of anticoagulation. Response to Octaplex was rapid with decline of INR within 10 min after Octaplex administration (from 6.1+/-2. to 1.5+/-0.3). Clinical response was graded as good in most patients (85%) and as moderate in the rest. Octaplex administration was uneventful in all patients. Following Octaplex administration, a small increase in F1+2 levels was observed in bleeding patients, whereas D-dimer level did not change significantly. We conclude that Octaplex is effective and safe in situations where rapid reversal of anticoagulation is needed.
Thrombosis Research 02/2004; 113(6):371-8. · 2.44 Impact Factor
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ABSTRACT: Severe obstetric complications, including preeclampsia, intrauterine growth retardation, abruptio placentae, and stillbirth, constitute a major cause of maternal and perinatal morbidity and death. The etiology of these severe obstetric complications is still unknown. However, the frequent finding of structural and thrombotic changes in placental capillaries, which lead to inadequate fetomaternal circulation and decreased placental perfusion, and the high prevalence of heritable or acquired risk factors for thrombosis found in women with these complications strongly suggest a cause-and-effect relationship. This review describes the recent findings on the association between these obstetric complications and the various thrombophilias, and recent therapeutic approaches. Aspirin, which was regarded as the drug of choice for the prevention of such obstetric complications, has proved to be ineffective in a large clinical trial. The encouraging observations on the efficacy of low-molecular-weight heparins, which are also included in the recently published guidelines of The American College of Chest Physicians, are summarized in this review. However, controlled clinical trials are still necessary to allow the development of better clinical standards.
Seminars in Thrombosis and Hemostasis 05/2003; 29(2):185-94. · 4.52 Impact Factor
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ABSTRACT: Splenectomy is the only treatment of ITP known to have "curative" effects in a substantial fraction of patients. However, the true long-term outcome is uncertain and controversial because published series have not adjusted for the duration of follow-up. This IRB-approved retrospective study included all patients with ITP who underwent splenectomy between 1988-1993 at three major medical centers and required a minimum postoperative 5-year follow-up. Complete response (CR) was defined as all postsplenectomy platelet counts >150 x 10(9)/L without treatment; partial response (PR) as platelet counts > or =50 x 10(9)/L without treatment; and failure as platelet counts <50 x 10(9)/L or receiving therapy after splenectomy. Seventy-five patients identified with ITP underwent splenectomy from 1988 to 1993. Three patients died prior to 5-year follow-up, and 56 of the 72 patients (78%) were evaluable with follow-up for five years or longer, median 7.5 years. The immediate postoperative complete remission rate was 77%; 57% of patients have remained in prolonged CR. Thirty-seven patients (66%) have not required any therapy after splenectomy. Eight patients had platelet counts >150 x 10(9)/L for 4-8.5 years before relapsing; no clear plateau was attained in the remission curve. There was no operative mortality. Ten patients (18%) reported minor postoperative bleeding episodes. No life-threatening infections, significant heart disease, or pulmonary hypertension developed after splenectomy in the 434 patient-years of follow-up. This study helps to define the long-term results of splenectomy for ITP.
American Journal of Hematology 02/2003; 72(2):94-8. · 4.67 Impact Factor
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ABSTRACT: To study the regulation of acetylcholinesterase (AChE) gene expression in human brain tumors, 3' splice variants of AChE mRNA and potentially relevant transcription factor mRNAs were labeled in primary astrocytomas and melanomas. AChE-S and AChE-R mRNA, as well as Runx1/AML1 mRNA accumulated in astrocytomas in correlation with tumor aggressiveness, but neither HNF3beta nor c-fos mRNA was observed in melanoma and astrocytomas. Immunohistochemistry demonstrated nuclear Runx1/AML1 and cellular AChE-S and AChE-R in melanomas, however, only AChE-S, and not the secreted AChE-R variant, was retained in astrocyte tumor cells. Runx1/AML1 revealed weak linkage with ACHE promoter sequences, yet enhanced ACHE gene expression in co-transfected COS1 cells. The p300 co-activator and the ACHE promoter's distal enhancer facilitated this effect, which was independent of much of the Runx1/AML1 trans-activation domain. Surprisingly, GASP, a fusion product of green fluorescence protein (GFP) and ASP(67), a peptide composed of the 67 C-terminal amino acid residues of AChE-S, localized to COS1 cell nuclei. However, GARP, the corresponding fusion product of GFP with a peptide having the 51 C-terminal residues of AChE-E or GFP alone, remained cytoplasmic. Runx1/AML1 exhibited improved nuclear retention in GASP-expressing COS1 cells, suggesting modulated nuclear localization processes. Together, these findings reveal brain tumor-specific regulation of both expression and cellular retention of variant ACHE gene products.
Oncogene 01/2003; 21(55):8428-41. · 6.37 Impact Factor
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ABSTRACT: Hematopoietic stress responses involve increases in leukocyte and platelet counts, implying the existence of stress responsive factors that modulate hematopoiesis. Acetylcholinesterase (AChE) is expressed in mammalian neurons and hematopoietic cells. In brain, it responds to stress by mRNA overexpression and alternative splicing, yielding the rare stress-associated "readthrough" AChE-R variant protein. This led us to explore the hematopoietic involvement of AChE-R and its cleavable C-terminal peptide ARP.
AChE mRNA variants were labeled in CD34(+) hematopoietic progenitor cells by in situ hybridization. ARP expression was detected by multicolor flow cytometry. Bromo-deoxyuracil incorporation and viable cell counts served to evaluate the proliferative effects of ARP and suppressive effects of the AChE antisense oligonucleotide AS1 on CD34(+) cells.
The distal enhancer, proximal promoter, and first intron of the human AChE gene include consensus binding sites for hematopoietically active and stress-induced transcription factors. CD34(+) cells from human cord blood were found to express all three variant AChE mRNAs, having different intracellular distributions. ARP was found in 5 to 15% of adult peripheral blood, bone marrow, and fetal CD34(+) cells (both committed CD38(+) and uncommitted CD38(-)) and in acute myeloid leukemia blasts. Externally supplied ARP by itself facilitated the proliferation of CD34(+) cells in an antisense suppressible manner. When combined with early-acting cytokines, ARP enhanced survival and expansion of CD34(+) cells up to 28 days in culture.
Our findings support ARP, the C-terminal peptide of AChE-R, as a new hematopoietic growth factor that may promote the myelopoietic expansion and thrombopoiesis characteristic of stress and may be used to enhance the efficiency of ex vivo expansion for bone marrow transplantation.
Experimental Hematology 11/2002; 30(10):1153-61. · 2.90 Impact Factor
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ABSTRACT: Umbilical cord blood (CB) provides an alternative source of hematopoietic progenitor cells for transplantation; however, prolonged thrombocytopenia remains a major obstacle due to the low numbers of megakaryocyte progenitor (Mk-prog) cells and their subsequent delayed engraftment. In this study, we improved techniques for enrichment, cryopreservation, and ex vivo expansion of Mk-prog cells from CB.
CB mononuclear cells (MNC) were isolated and Mk-prog enriched by sedimentation on gelatin followed by centrifugation with Ficoll-Hypaque and cryopreserved. The capacity of MNC to produce Mk-prog cells, assessment of CD34(+) and Mk-prog expansion in liquid culture, and analysis of the cell populations by flow cytometry were studied in cryopreserved separated CB and compared to whole CB and freshly separated samples.
Excellent viability of greater than 85% was maintained after cryopreservation of separated CB. The number of colony-forming Mk-prog, myeloid, and erythroid progenitor cells did not decrease with cryopreservation. Flow cytometric analysis of cryopreserved cells revealed significant removal of the residual red blood cells while maintaining complete recovery of CD34(+), CD41(+) (Mk), myeloid, and T and B cells compared to noncryopreserved CB cells. There was no difference in the ability of separated cryopreserved MNC CB cells to be expanded in short-term liquid cultures.
The conditions defined here for cryopreservation of gelatin/Ficoll-Hypaque separated CB, followed by ex vivo expansion of MNC, allowed complete recovery of proliferating CD41(+), CD34(+), Mk-prog cells, and other hematopoietic progenitors. Mk-prog cell expansion just before the scheduled transplantation is easily applicable by this technically simple and economical procedure that requires only an aliquot of red cell cell-depleted MNC to be separated from the CB unit before cryopreservation.
Experimental Hematology 10/2002; 30(9):1079-87. · 2.90 Impact Factor
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Amiram Eldor
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ABSTRACT: Thromboembolic disease is a rare, but important, complication of pregnancy that remains a leading non-obstetric cause of maternal death. The prevention and management of venous thromboembolism (VTE) in pregnant women is a complex area of medicine: a balance must be found between protecting the health of the mother and minimizing the risk to the unborn fetus. Until now, unfractionated heparin has been regarded as the drug of choice for the prevention and treatment of VTE during pregnancy. However, because of its significant side effects (osteoporosis and heparin-induced thrombocytopenia), the inconvenient mode of administration and need for monitoring, unfractionated heparin is now being replaced by low-molecular-weight heparin (LMWH). There is a convincing body of clinical evidence from well-designed studies and prospective case series that supports the efficacy and safety of LMWH in pregnant women. There are also encouraging observations on the efficacy of LMWH in the prevention of severe obstetric complications, which are frequently associated with inherited or acquired thrombophilias. The recently-published guidelines of The American College of Chest Physicians (ACCP), summarized in this review, allows the development of higher clinical standards. However, there is concern over the greater cost of LMWH compared with unfractionated heparin and oral anticoagulants, and cost-effectiveness studies are needed.
European Journal of Obstetrics & Gynecology and Reproductive Biology 09/2002; 104(1):3-13. · 1.97 Impact Factor
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ABSTRACT: Several experimental systems have been applied to investigate the development of new blood vessels. Angiogenesis can be followed ex-vivo by culturing explants of rat aorta 'rings' in biomatrix gels. This angiogenesis system was modified for the study of viral vector mediated gene transfer, using adenovirus, vaccinia- and retroviral vectors. Two modifications were introduced to the model in order to facilitate efficient viral mediated gene transfer, (i) placing the aorta ring on top of a thin layer of collagen such that the angiogenic tissue will be accessible to the viral vector; and (ii) infection of the aorta rings prior to embedding them into the collagen matrix. While adenovirus and vaccinia vectors infected efficiently the aorta rings they induced cell death. Subsequent gene transfer experiments were, therefore, carried with retroviral vectors containing vascular endothelial growth factor (VEGF) and the beta-interferon (IFN) genes. Overexpression of VEGF enhanced significantly microvessel sprouting, while overexpression of IFN-beta induced an antiviral effect. The experimental system described in this study can facilitate the application of other viral vectors to the study of genes that may regulate the complex angiogenic process and thereby open new avenues for vascular gene therapy.
Journal of Virological Methods 09/2002; 105(1):1-11. · 2.01 Impact Factor
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ABSTRACT: Heparin-induced thrombocytopenia (HIT) occurs in 1-5% of patients treated with heparin. The pathogenesis involves the formation of antibodies to heparin-platelet factor 4 complexes, and the major clinical sequelae are thrombotic. Diagnosis is based on a combination of clinical and laboratory data. Treatment consists of stopping heparin, but, insofar as the risk of thrombosis remains high, treatment by alternative antithrombotic agents is indicated. Most clinical experience has been with danaparoid sodium and hirudin. The use of low-molecular-weight heparins (LMWH) in subsequent HIT episodes has been described, but is not recommended, especially with the introduction of new agents, such as oral thrombin inhibitors and pentasaccharides, which are hoped to reduce the use of heparins and the occurrence of HIT.
Autoimmunity Reviews 09/2002; 1(4):183-9. · 6.62 Impact Factor
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ABSTRACT: Heparanase is a heparan-sulfate-degrading endoglycosidase that has important roles in various biological processes, including angiogenesis, wound healing and metastatsis. Human heparanase is synthesized as a 65 kDa latent precursor, which is proteolytically processed into a highly active 50 kDa form. Extracellular heparanase is found in various tissues and is utilized by both normal cells and metastatic cancer cells to degrade heparan sulfate moieties in basement membranes and extracellular matrices. This study characterizes the processing and trafficking events associated with cellular activation of extracellular heparanase. We show that primary human fibroblasts are capable of binding and converting the 65 kDa heparanase precursor into its highly active 50 kDa form, concomitantly with its cytoplasmic accumulation. Heparanase uptake depends on the actin cytoskeleton integrity, resulting in a prolonged storage of the enzyme, mainly in endosomal structures. Heparanase endocytosis and its proteolytic activation are independent processes, indicating that heparanase cleavage is a cell surface event. Heparin completely inhibits heparanase endocytosis but only partially inhibits its association with the cells, suggesting that cell surface heparan sulfate moieties play a specific role in its endocytosis. Cellular binding and uptake of extracellular heparanase control its activation, clearance rate and storage within the cells.
Journal of Cell Science 06/2002; 115(Pt 10):2179-87. · 6.11 Impact Factor
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ABSTRACT: To determine the risk of thrombophilias in women with unexplained intrauterine fetal deaths (IUFD).
All women with IUFD at 27 weeks' gestation or greater were initially assessed during a period of 26 months. Subjects with multiple pregnancies, congenital anomalies, intrauterine infection, chorioamnionitis, immune hydrops, diabetes mellitus, previous thromboembolism, and severe hypertensive disease were excluded. The remaining 40 women with unexplained IUFD (study group) were matched for age and ethnicity with 80 healthy women who had at least one normal pregnancy (control group). All participants were tested at least 2 months after delivery for mutations of factor V Leiden, prothrombin gene, methylenetetrahydrofolate reductase, and for deficiencies of protein S, protein C, and antithrombin III. They were also tested and found to be negative for anticardiolipin antibodies.
The gestational age at delivery and birth weight were significantly lower in the study group. The prevalence of inherited thrombophilias was 42.5% in the study group compared with 15% in the control group (odds ratio 2.8, 95% confidence interval 1.5, 5.3, P =.001). The prothrombin mutation and protein S deficiency rates were significantly higher in the study group (odds ratio 2.3, 95% confidence interval 1.3, 4.0, and odds ratio 3.2, 95% confidence interval 2.4, 4.1, respectively).
Third-trimester IUFD is significantly associated with thrombophilias. These findings suggest that thrombophilia work-ups should be part of IUFD investigations and may have therapeutic and prognostic implications in future pregnancies.
Obstetrics and Gynecology 06/2002; 99(5 Pt 1):684-7. · 4.73 Impact Factor
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ABSTRACT: Runx1/AML1, a chromosome 21q22 hematopoietic regulator, is frequently translocated in leukemia. Its protein product, a relatively weak transcriptional activator, becomes an effective transcriptional enhancer or repressor, when co-operating with transcriptional co-activators or co-repressors. Runx1/AML1 association with its partners is disrupted in leukemia. For example, Runx1/AML1 mutations and translocations (e.g. t(8;21), t(12;21) and t(3;21)) impair binding of Runx1/AML1-CBFbeta complexes to Runt motifs in myelopoietically active promoters, preventing normal hematopoiesis. However, Runx1/AML1-associated translocations are not leukemogenic in animal models, suggesting the involvement of yet unidentified regulatory proteins. New candidates are cholinesterases, inhibition of which increases leukemic risk in a manner potentially associated with Runx1/AML1.
Leukemia Research 04/2002; 26(3):221-8. · 2.92 Impact Factor
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ABSTRACT: Chronic myeloid leukemia (CML), in most of the cases, is the molecular consequence of the t(9,22) translocation, resulting in the Philadelphia (Ph) chromosome and the creation of the fusion gene BCR-ABL. The fusion gene is translated to the protooncogen BCR-ABL, a constitutively activated tyrosine kinase that is linked to the malignant transformation. Thus, this tyrosine kinase became an attractive target for drug design. The development of the novel investigational drug STI 571 is based on its potent and selective ability to inhibit this fusion tyrosine kinase. In preclinical studies, STI 571 selectively inhibited the growth of CML cells that carry the Ph chromosome. In this review we discuss the drug development and design, its mechanism of action, the preclinical studies and the results of phase I and II clinical trials.
Harefuah 03/2002; 141(2):158-62, 222.
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ABSTRACT: Heparin-induced thrombocytopenia (HIT) is a serious complication that occurs in approximately 1-5% of patients treated with heparin and may be associated with severe thrombotic events. HIT is mediated by antibodies directed mostly to epitope(s) formed by complexes between heparin or other anionic mucopolysaccharides and platelet factor 4 (PF4). Anti-PF4/heparin IgG antibodies from six patients with HIT were affinity purified and assessed for interaction with human microvascular and macrovascular endothelial cells (EC). The antibodies directly activated primary cultures of human bone marrow microvascular EC (HBMEC) and SV40 immortalized HBMEC (TrHBMEC) only in the presence of PF4, but did not activate macrovascular human umbilical vein EC (HUVEC) under the same conditions. These antibodies were found to bind to TrHBMEC through the F(ab)(2) portion of the anti-PF4/heparin IgG. TrHBMEC activation was characterized by an augmented release of IL-6, von Willebrand factor, soluble thrombomodulin, and by an elevated expression of the adhesion molecules P-selectin, E-selectin and vascular cellular endothelial molecule-I to different degrees. Enhanced monocyte adhesion to PF4/heparin antibody-treated TrHBMEC (33-72% adhesion) was also observed. None of these effects occurred with unstimulated HUVEC. However, pre-treatment of HUVEC with tumor necrosis factor-alpha resulted in the same changes observed with microvascular EC exposed to the HIT antibodies. Our findings indicate that anti-PF4/heparin antibodies directly activate microvascular EC while interaction with macrovascular EC requires pre-activation. These results may explain some of the specific clinical manifestations in HIT.
International Immunology 03/2002; 14(2):121-9. · 3.41 Impact Factor
