bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of etoposide, ifosfamide, and mitoxantrone for the treatment of resistant adult acute lymphoblastic leukemia
Authors: Schiller Gary , Lee Myung , Territo Mary , Gajewski James , Nimer Stephen
Published: February 2007

Although combination chemotherapy induces complete remission in 60–90% of adults with acute lymphoblastic leukemia, only 20–45% of patients remain in continued remission 5 years from diagnosis. For patients with a short first remission, multiple relapses, or patients with disease refractory to initial induction chemotherapy, few salvage treatments are successful. To improve the results of salvage therapy we studied the efficacy and toxicity of a combination of etoposide (100 mg/m2 IV qd × 5), ifosfamide (1.5 g/m2/d × 5), and mitoxantrone (8 mg/m2/d IV × 3) in 11 adult patients with relapsed or refractory ALL. The median follow‐up of all patients completing therapy is 208 days (30–484+ days). Eight of 11 (73%; 95% confidence interval 45–92%) achieved a complete remission, two patients failed to enter remission, and one patient died of multiorgan system failure shortly after receiving therapy. Median DFS is 96 days and median survival from remission is 234 days. Five patients who achieved CR subsequently relapsed with a median time to relapse of 80 days (50–151 days). Median time to granulocyte > .5 × 109/L was 28 days (21–46 days) and the median time to platelet recovery > 20 × 109/L was 24 days (21–39 days). Although gastrointestinal toxicity was common, no patient developed severe cardiac, hepatic, pulmonary, or neurologic complications. These results demonstrate that the combination of etoposide, ifosfamide, and mitoxantrone can be used as an effective salvage therapy for patients with resistant ALL.
α‐interferon therapy for severe chronic idiopathic thrombocytopenic purpura in children
Authors: Cohn Richard J. , Schwyzer Rosemarie , Poole Janet E. , Hesseling Peter B. , Naidoo Joan , Van Heerden Corrieta
Published: February 2007

We report the use of α2b‐interferon in 15 children with symptomatic, chronic idiopathic thrombocytopenic purpura, who did not respond to standard therapy. The platelet count increased in nine children during therapy. In six children the increase lasted less than 6 weeks. An increased platelet count was seen when a higher dose was used in two of four initial nonresponders. One responder who relapsed had an identical response when retreated with the same dose. No significant side effects were documented. Further studies are required to establish the optimal dose and administration schedule of α2b‐interferon for use in children with chronic idiopathic thrombocytopenic purpura.
Effects of continuous high dose rhgm‐csf infusion on human monocyte activity
Authors: Perkins Raymond C. , Vadhan‐Raj Saroj , Scheule Ronald K. , Hamilton Raymond , Holian Andrij
Published: February 2007

In this study we describe the time‐dependent effects of a high dose (750 (μg/ml/24 hr) continuous infusion of recombinant human granulocyte‐macrophage colony‐stimulating factor (rhGM‐CSF) on monocyte number, cytokine release, and superoxide anion production. Blood was taken from patients prior to rhGM‐CSF infusion (day 0), and on days 1,7, and 14 of infusion. The mean concentration of monocytes per ml of blood increased progressively from 4.3 × 105 on day 0 to 21 × 105 on day 14 of infusion. There was no significant change in the basal release of tumor necrosis factor α (TNF‐α) or interleukin 1β (IL‐1β) induced by rhGM‐CSF. However, the lipopolysaccharide (LPS)‐stimulated release of TNF‐α by monocytes increased significantly on day 1 of infusion, and by day 14 had increased 8‐fold. IL‐1β release from LPS‐stimulated monocytes increased slightly by day 7, and by almost 10‐fold by day 14 of infusion. When maximally stimulated with phorbol dibutyrate, the monocytes demonstrated an increased (although not significant) capacity to produce superoxide anion on days 7 and 14 of infusion. No change in basal superoxide anion production was seen at any day of infusion. These GM‐CSF‐induced changes in stimulated cytokine and superoxide anion release could not be reproduced by treating monocytes with rhGM‐CSF in vitro. In summary, a two week, high dose infusion of rhGM‐CSF resulted in increases in circulating monocyte concentration, and in the stimulated release of TNF‐α and IL‐1β, and superoxide anion production from these monocytes. These primed monocytes could enhance the ability of neutropenic patients to fight infection.
Successful alpha‐2b‐interferon therapy for chronic neutrophilic leukemia
Authors: Meyer S. , Feremans W. , Cantiniaux B. , Capel P. , Huygen K. , Dicato M.
Published: February 2007

The authors report two patients with characteristic features of chronic neutrophilic leukemia (CNL) treated with alpha‐2b‐interferon (IFN) (Schering‐Plough). At initiation of therapy, both patients had progressive disease and presented with large tumors. A rapid reduction of the tumor mass and a long‐term stabilisation of the myeloproliferative disorder was obtained (therapy duration 16 and 26 months, respectively, and presently ongoing). In one patient, the dose of IFN could be significantly reduced during maintenance without relapse. Neither presented infectious or hemorrhagic complications under therapy. Alpha‐2b‐interferon is active and safe in CNL, even pretreated and progressive. It can also correct the neutrophil and natural killer functional defects frequently observed in CNL.
Hb Saint Nazaire (β103[G5]Phe→Ile): A new example of polycythemia due to a hemoglobin variant with increased oxygen affinity
Authors: Wajcman H. , Kister J. , M'Rad A. , Promé D. , Milpied N. , Rapp M. J. , Harousseau J. L. , Riou J. , Bardakdjian J. , Galacteros F.
Published: February 2007

Hb Saint Nazaire [β103 (G5) Phe→lle] was found in four apparently unrelated French families. The five patients carrying this hemoglobin have been detected because of a moderate erythrocytosis. The structural abnormality of Hb Saint Nazaire concerns the same residue as in Hb Heathrow [β103 (G5) Phe→Leu)]. A comparative functional study between these two variants showed that the increase in oxygen affinity is much lower in Hb Saint Nazaire than in Hb Heathrow. The replacement of phenylalanine G5, which is localized within the heme pocket, by a leucine abolishes several contacts between the heme and the globin and leads to an environment of the heme having some similarities with that observed in myoglobin. In contrast, the replacement of G5 by an isoleucine is likely to introduce less structural modifications. © 1993 Wiley‐Liss, Inc.
Cd7, CD34‐positive stem cell leukemia arising in agnogenic myeloid metaplasia
Authors: Tasaka Taizo , Nagai Masami , Murao Satoshi , Yamaguchi Masahiro , Kitanaka Akira , Sasaki Kazunori , Murata Michio , Tanaka Terukazu , Kuwabara Hiroko , Ikeda Kazuma , Takahara Jiro , Irino Shozo
Published: February 2007

Agnogenic myeloid metaplasia (AMM) is a chronic myeloproliferative disorder arising from a single hematopoietic cell. Approximately 5% of reported cases of AMM have terminated in leukemic crisis; however, the precise characteristics of the leukemic cells have rarely been reported. We report a case of AMM that occurred in a 42‐year‐old man and was complicated by leukemic transformation. The leukemic cells wer morphologically lymphoblastoid cells with a negative reaction to peroxidase staining, and phenotypically characterized as CD7+, CD34+, HLA‐DR+, CD4−, CD8−, CD10−, CD13−, and CD33−. Southern blot analysis revealed that T cell receptor‐β, γ, and immunoglobulin heavy chain genes in leukemic cells were retained in germ‐line configuration. These observations suggest that leukemic cells in our case involved early hematopoietic stem cells rather than those strictly committed to myeloid or lymphoid precursors. To our knowledge, this is the first report of stem cell leukemia arising in a patient with AMM. © 1993 Wiley‐Liss, Inc.
Presence of serum antibodies to coagulation protein C in patients with systemic lupus erythematosus is not associated with antigenic or functional protein c deficiencies
Authors: Ruiz‐Arguelles Alejandro , Vazquez‐Prado Jose , Deleze Margarita , Perez‐Romano Beatriz , Drenkard Cristina , Alarcon‐Segovia Donato , Ruiz‐Arguelles Guillermo J.
Published: February 2007

Antibodies directed to immunopurified coagulation protein C (PC) were investigated in serum samples from 108 patients with systemic lupus erythematosus (SLE) and found in 12 of them. However, their presence was not associated with antigenic or functional deficiencies of PC, which were documented in 6 and 17 patients, respectively. © 1993 Wiley‐Liss, Inc.
Mean platelet volume improves upon the megathrombocyte index but cannot replace the blood film examination in the evaluation of thrombocytopenia
Authors: Vukelja Svetislava J. , Krishnan Jayashree , Diehl Louis F.
Published: February 2007

The measurement of the number of platelets larger than 3 microns (megathrombocyte index) is the first element in the evaluation of thrombocytopenia. This is currently performed by counting the number of large platelets on the peripheral blood film. The MPV (mean platelet volume) is an automated measurement of the platelet volume. This study examines the mean values, correlations, sensitivity, specificity and the receiver operating characteristic curve (comparison of two tests) to determine which of these tests better separates the production state. For increased vs. decreased production, the MPV was 10.0 + 1.9 fL and 8.0 + 1.5 fL (P < .0001) respectively and the megathrombocyte index (MEGA) was 19.0 + 17.6% and 11.5 + 14.9% (P < .007) respectively. The correlation with the state of production was better for MPV (R = .47) than for MEGA (R = .20). For the MPV a sensitivity of 80% occurred with the MPV ⩾ 8.4 fL with a specificity of 71%. For a MEGA ⩾ 6%, the sensitivity was 80% but the specificity was 43%. For any MPV the sensitivity and specificity were better than for any MEGA. The Receiver Operating Characteristic Curve demonstrated that the MPV is a better test than the MEGA for separating the production into increased and decreased states. The MPV is a better test than the MEGA and will add to, but not replace, examination of the peripheral blood film in the diagnosis of thrombocytopenia. © 1993 Wiley‐Liss, Inc.
Increased levels of vascular endothelial cell markers in thrombotic thrombocytopenic purpura
Authors: Wada Hideo , Kaneko Toshihiro , Ohiwa Michiaki , Tanigawa Motoaki , Hayashi Tatsuya , Tamaki Shigehisa , Minami Nobuyuki , Deguchi Katsumi , Suzuki Koji , Nakano Takeshi , Shirakawa Shigeru
Published: February 2007

We found that patients with thrombotic thrombocytopenic purpura (TTP) have significantly elevated plasma thrombin antithrombin III complex (TAT) and FDP‐D‐dimer levels, while the plasmin‐α2 plasmin inhibitor complex (PIC) level was only slightly increased. The tissue‐type plasminogen activator (t‐PA) level was increased, but it was well correlated with the plasminogen activator inhibitor‐1 (PAl‐l) level. These findings suggest that hypercoagulable and hypofibrinolytic states coexist in these patients, in contrast to patients with disseminated intravascular coagulation, who exhibit coexisting hypercoagulable and hyperfibrinolytic states. Levels of vascular endothelial cell markers, such as PAl‐l, thrombomodulin (TM), and t‐PA, were increased at the onset of TTP, but the level of von Willebrand factor (vWF) antigen was not increased. The outcome in TTP patients was correlated with plasma t‐PA and TM levels but not with TAT or PIC. These results suggest that vascular endothelial cell markers, such as TM and t‐PA, are released from injured or stimulated endothelial cells, reflecting the degree of vascular endothelial damage, and that the main factor in the pathogenesis of TTP is vascular endothelial cell injury. © 1993 Wiley‐Liss, Inc.
Flow cytometric analysis of changes in cytoskeletal proteins during platelet destruction and activation using a monoclonal antibody against platelet myosin
Authors: Yamaguchi Kazuyuki , Nomura Shosaku , Kido Hirofumi , Kawakatsu Toshihiro , Fukuroi Tsutomu , Suzuki Masahiro , Hamamoto Kenjiro , Yanabu Mutsumasa , Kokawa Terutoshi , Yasunaga Kojiro
Published: February 2007

We developed a new monoclonal antibody directed against platelet myosin (NNKY6‐19). Using this antibody, we analyzed platelet cytoskeletal changes related to stimulation with thrombin and to long‐term storage. Immunoelectron microscopy showed increased binding of NNKY6‐19 to pseudopods and the open canalicular system during treatment with thrombin (0.1 U/ml) and during storage for 7 days. Flow cytometry also showed increased binding to platelets by NNKY6‐19 and an antiactin monoclonal antibody during storage. The binding of NNKY6‐19 showed an increase greater than that with the antiactin antibody after storage of platelets for 7 days and after thrombin treatment. These findings indicated that the increased binding of NNKY6‐19 had some relationship to changes in intracellular myosin and platelet morphology. Thus use of NNKY6‐19 allowed analysis of subtle changes related to platelet activation, which differed from those detected by antibodies against platelet glycoproteins or by the antiactin antibody. This antibody appears to provide a simple method for studying changes in platelet cytoskeletal and surface proteins. © 1993 Wiley‐Liss, Inc.
Synergistic effect of heme and IL‐1 on hematopoietic stromal regeneration after radiation
Authors: Lutton John D. , Chertkov Joseph L. , Jiang Shanlong , Kappas Attallah , Levere Richard D. , Abraham Nader G.
Published: February 2007

Results from this study show that a combination of heme and interleukin‐1 (IL‐1) treatment resulted in the most improved recovery of hematopoietic‐stromal regeneration after sublethal irradiation. Less pronounced effects were obtained when heme or IL‐1 were given singly. Sublethal irradiation of mice produced an initial (as early as day 1) intense depression of the hematopoietic system as evidenced by leukopenia. In vivo treatment of animals with heme in combination with IL‐1, accelerated hematopoietic and stromal regeneration as determined by hematopoietic spleen colony forming unit assay (CFU‐S), erythroid (BFU‐E), myeloid (CFU‐GM) clonal cultures, long‐term bone marrow cultures (LTBMC), and the ability to regenerate hematopoiesis by ectopic (renal) stromal hemopoietic transplantation. Sixteen days after irradiation, leukocyte levels in heme and IL‐1 treatment groups were higher than non‐treated animals and were near normal values by 27 days. One day after irradiation, the capacity of stromal progenitors to form new bone and hematopoietic cells (ectopic foci) was severaly impaired, but recovered after 2–4 weeks. This recovery process was accelerated in heme and IL‐1‐treated animals. BFU‐E, CFU‐GM, and CFU‐S capacity was also severely impaired in all animals 1–27 days after irradiation. CFU‐S was only 0.15% of control by day 1 and 5% of control by day 16. Treatment with heme or IL‐1 improved recovery by as much as 70% after 27 days of irradiation. A similar but enhanced recovery was seen for BFU‐E and CFU‐GM, with erythroid recovery the best. Total cellularity, adherent cell layer (ACL) formation, and donogenic capacity by LTBMCs (10 weeks) derived from irradiated animals was severely reduced, whereas the hematopoietic capacity by LTBMCs derived from heme‐ and IL‐1‐treated animals had recovery values similar to non‐irradiated controls. These results suggest therapeutic use of heme and IL‐1 after chemotherapy or bone marrow depression may be beneficial. © 1993 Wiley‐Liss, Inc.
Macrophage‐megakaryocyte interaction in bone marrow after high‐dose intravenous immunoglobulin therapy
Authors: Saito Nagahito , Takemori Nobuo , Hirai Katsuyuki , Onodera Ryuichi , Watanabe Shinji , Namiki Masayoshi
Published: February 2007

Localization of IgG in bone marrow after high‐dose intravenous immunoglobulin therapy (IVIG) was investigated via light and electron microscopy. IgG was incorporated into the cytoplasm of various types of bone marrow cells of all the three lineages, particularly in reticulum cells, fat cells, and megakaryocytes. In addition, both reticulum cells and fat cells showed many elongated cytoplasmic protrusions, which were in contact with the various types of blood cells, especially the megakaryocytes. A filamentous structure was also seen near the point of contact between the cells. Ultrastructural changes of macrophages in bone marrow after IVIG suggest that these cells were activated by IVIG. © 1993 Wiley‐Liss, Inc.
Weak n activity of en(a−) human erythrocyte membranes
Authors: Shinozuka Tatsuo , Miyata Yoshihisa , Ohyama Kunio , Takei Setsuko , Yamakawa Toshio , Kurihara Katsuyoshi , Yanagida Junichi
Published: February 2007

The propositus's erythrocytes with phenotype En(a−), which was found for the first time in a Japanese family, reacted more weakly with anti‐N serum than the ordinary phenotype N erythrocytes. The En(a−) erythrocytes lack the major membrane sialoglycoprotein (glycophorin A) as demonstrated by Bio‐Gel 1.5m gel filtration from active sialoglycoproteins, which were isolated from En(a−) erythrocyte membranes by the method of lithium diiodosalicylate (LIS)‐phenol extraction. It is suggested from observation via enzymelinked immunosorbent assay (ELISA) that N activity is derived from the glycophorin B molecule on En(a−) erythrocyte membranes. © 1993 Wiley‐Liss, Inc.
TNF‐α induces spreading of B‐CLL via the CD11C/CD18 molecule
Authors: Van Kooten Cees , Rensink Irma , Aarden Lucien , Van Oers Rien
Published: February 2007

Activation of malignant B cells can lead to extensive morphological changes of these cells. A combination of PMA and TNF‐α can induce adherence of purified B‐CLL cells, which acquire a dendritic cell‐like appearance. This phenomenon that we have termed spreading, is accompanied by upregulation of expression of both β1 and β2 integrin molecules. Spreading was inhibited by the addition of antibodies against CD18 or CD11c. In other B cell malignancies (HCL and NHL), morphological changes could be induced by PMA in the absence of TNF‐α. Culturing in the presence of prednisolone resulted in an inhibition of spreading, most likely mediated via a down regulation of CD18 and CD11c expression. These data indicate that the CD11c/CD18 complex might be important for the adhesive properties of B cells. © 1993 Wiley‐Liss, Inc.
Peripheral neuropathy in IgM monoclonal gammopathy and wäldenstrom's macroglobulinemia: A frequent complication in elderly males with low MAG‐reactive serum monoclonal component
Authors: Baldini Luca , Nobile‐Orazio Edoardo , Guffanti Andrea , Barbieri Sergio , Carpo Marinella , Cro Lilla , Cesana Bruno , Damilano Isabella , Maiolo Anna T.
Published: February 2007

Peripheral neuropathy (PN) is a frequent complication during primary macroglobulinemia (PM), whose immunological genesis has been suggested by various authors. This study involved 65 PM patients (44 men and 21 women aged 35‐78), diagnostlcally divided into MGUS (31 cases), and indolent (IWM, 24 cases) or symptomatic (WM, 10 cases) Waldenstrom macroglobulinemia groups. All patients underwent neurological examination, including electrodiagnostic evaluation and the determination of the serum titre of antimyelin‐associated glycoprotein (MAG). An evaluation was made of the prevalence of PN and its correlation with a series of hematological variables.

The prevalence of PN was 31.6%: of those with PN, 73.1% manifested both clinical and electrophysiological signs of PN, primarily of the demyelinating type. Significant correlations emerged between the presence of PN and sex (M vs. F P = 0.0001), advanced age (P = 0.049), low MC levels (P = 0.025), high anti‐MAG titres (P = 0.001) and high Hb levels (P = 0.001). No significant correlation with the diagnostic definition of PM was found, although the majority of cases with (particularly demyelinating) PN were MGUS or IWM. At multivariate analysis, the presence of PN significantly correlated with sex (P = 0.0001), age (P = 0.019), and anti‐MAG titre (P = 0.001).

Ten of the 26 PN cases showed no MAG reactivity. Significant correlations between PN and low serum MC levels/high MAG reactivity support the hypothesis of the antibody‐mediated origin of many PN, and that the presence of PN depends on the characteristics the proliferating pathological B clone, rather than on the tumor burden of the form of macroglobulinemia. Clinically, our data reconfirm the frequency of PN during PM and indicate simple clinicohematological variables useful for identifying patients at high neuropathic risk. © 1994 Wiley‐Liss, Inc.
Quantities of αQ chain variants in heterozygotes with and without a concomitant β‐thalassemia trait
Authors: Qin W.‐B. , Baysal E. , Wong K. F. , Molchanova T. P. , Pobedimskaya D. D. , Sharma S. , Wilson J. B. , Huisman T. H. J.
Published: February 2007

We have analyzed the quantities of αx chain‐containing hemoglobins (αxβ2 and α2xβ2,) in 14 heterozygotes for Hb Q‐India [α64(E13)Asp→His] or Hb Q‐Thalland [α74(EF3)Asp→Hls]; both amino acid replacements are the result of mutations in the α1‐globin gene. Five of these persons (three with Hb Q‐India and two with Hb Q‐Thailand) had an additional β°‐thalassemia heterozygoslty. The average quantities for Hb Q + Hb Q2 in the four groups were 17.2% (Q/αα; βA/βA), 9.5% (ααQ/αα; βA/β°Th), 26.8% (‐αQ/αα;βA/βA), and 16.95% (‐αQ/αα; βA/β°Th). These variations can best be explained by a posttranslational control mechanism; an imbalance in the αA, αQ, and βA chain ratio will favor the αzQβz formation when an α‐thalassemia is present and will reduce its formation in the presence of a β‐thalassemia heterozygosity. © 1994 Wiley‐Liss, Inc.
Hemophilic pseudotumor: Multicenter experience over 25‐year period
Authors: Magallón M. , Monteagudo J. , Altisent C. , Ibáñez A. , Rodriguez‐Pérez A. , Riba J. , Tusell J. , Martin‐Villar J.
Published: February 2007

Pseudotumor is an infrequent manifestation of bleeding diathesis seen in hemophiliacs, the management of which is still controversial. To ascertain the effectiveness of the main therapies of choice, we have reviewed 1,831 patients affected by hemophillas A (1,108) and B (172), von Willebrand's disease (329), and other miscellaneous coagulopathles (222) diagnosed between 1965 and 1990 in a multicentric, retrospective study. Pseudotumor was proven in 21 patients. Replacement therapy was given in 15 cases as the first therapeutic approach, with complete success attained in only two, whereas surgery, which was carried out in 14 patients, completely resolved the process in eight (P = 0.017). Patients over 40 years of age demonstrated worse prognosis than younger patients (P = 0.02), but no other clinical parameters were shown to have influenced the patients' evolution. Surgical management was the most effective treatment for pseudotumor, although more conservative therapies cannot be overlooked in selected cases. © 1994 Wiley‐Liss, Inc.
Von willebrand factor availability in platelet concentrates stored for 5 days
Authors: Cesar Jesús M. , Garcia‐Avello Angel , Monteagudo Juán , Espinosa José I. , Lodos José C. , Castillo Ricardo , Navarro José L.
Published: February 2007

Von Willebrand factor (vWF) availability was assessed in platelet concentrates (PCs). After 5 days of storage, 82 ± 9% of basal levels of ristocetin cofactor activity (vWF:RCo) remained in PCs. vWF antigen (vWF:Ag) increased up to 166 ± 38% (P < 0.05) In the same period. Autoradiograph pattern of vW:Ag showed an increase in low molecular weight multimers, and fast migrating multimeric forms were visualized by crossed immunoeiectrophoresis on day 5. Studies carried out in platelet free plasma stored as PCs showed similar changes in vWF:RCo but increments in vWF:Ag were not detected. These data indicate that PCs maintain vWF:RCo levels of clinical value even after 5 days of storage and suggest that vWF comes out from platelets to plasma during storage. © 1994 Wiley‐Liss, Inc.
Changes in longevity and causes of death among persons with hemophilia A
Authors: Chorba Terence L. , Holman Robert C. , Strine Tara W. , Clarke Matthew J. , Evatt Bruce L.
Published: February 2007

To examine recent changes in longevity and the causes of death among persons with hemophilia A, we evaluated death certificate data for persons who died in the United States from 1968 through 1989 and had hemophilia A or congenital Factor VIII disorder (ICD code 286.0) listed on the death certificate as one of the multiple causes of death. Multiple‐cause‐of‐death mortality data for the United States from 1968 to 1989 were examined to compare death rates by year, focusing on death rates and causes of death for 1979‐1981, 1983‐1985, and 1987‐1989. Gender, age group, race, geographic region, and median age at death of persons with hemophilia A and human immunodeficiency virus (HIV)‐related disease listed as a cause of death were compared with those with hemophilia A without HIV‐related disease. From 1968 through 1989, 2,792 hemophilia A deaths were reported. The death rate increased from 0.5 to 1.3 per 1,000,000 persons. From 1979‐1981 through 1987‐1989, mortality increased in all age groups above 9 years of age and age at death shifted markedly to lower ages. Median age at death decreased from 57 years in 1979‐1981 to 40 years in 1987‐1989. The percentage of deaths due to hemorrhage or diseases of the circulatory system decreased markedly as the result of the increase in deaths associated with HIV infection or infections other than HIV infection. Spread of HIV‐1 infection in persons with hemophilia A has disrupted the reduction in mortality seen with factor replacement therapy, implementation of home care, and use of comprehensive hemophilia treatment centers. It is hoped that advances in the care of HIV‐infected persons will improve survival in the hemophilia community. © 1994 Wiley‐Liss, Inc.
Varying populations of CD59‐negative, partly positive, and normally positive blood cells in different cell lineages in peripheral blood of paroxysmal nocturnal hemoglobinuria patients
Authors: Fujioka Seitoku , Yamada Teruo
Published: February 2007

CD59‐antigen expression on the surface membranes of erythrocytes, granulocytes, monocytes, lymphocytes, and platelets was determined by flow cytometry in 34 healthy controls and 17 patients with paroxysmal nocturnal hemoglobinuria (PNH). In all PNH patients, CD59‐negative erythrocytes accounted for > 10% of the total erythrocyte population. Two erythrocyte populations (CD59‐negative and normally positlve or CD59‐negative and partly positive), three populations (CD59‐negative, partly positive, and normally positive), and one population (CD59‐negative) were demonstrated in ten, six, and one patients, respectively. However, CD59‐negative granulocytes did not account for > 10% of the total granulocytes in two patients, and one of them had only a CD59 normally positive granulocyte population. A particular granulocyte population extended over both CD59‐negative and partly positive areas was shown in two patients. Two populations (CD59‐negative and normally positive) and one population (CD59‐negatlve) were demonstrated in monocytes and lymphocytes. CD59‐negative lymphocytes accounted for >50% of the total lymphocytes in only two patients. Three patients had a CD59 normally positive lymphocyte population. Percentages of CD59‐positive platelet population in normal controls were widely various. Therefore, it was usually difficult to discriminate between PNH‐affected and normal platelets. Thus, the flow cytometric profiles of CD59‐antigen expression varied not only between PNH patients but between cell lineages. The present results and our prior study indicate that CD59 flow cytometry using erythrocytes and granulocytes is most suitable for diagnosing PNH. © 1994 Wiley‐Liss, Inc.
Topical thrombin and acquired coagulation factor inhibitors: Clinical spectrum and laboratory diagnosis
Authors: Ortel Thomas L. , Charles Linda A. , Keller Frank G. , Marcom P. Kelly , Oldham H. Newland , Kane William H. , Macik B. Gail
Published: February 2007

Topical bovine thrombin preparations are used extensively in cardiovascular, neurosurgical, and otolaryngologic procedures. Patients who are treated with these topical thrombin preparations may develop antibodies to bovine coagulation factors that may cross‐react with the endogenous human clotting proteins. We have identified four patients with acquired factor inhibitors following exposure to topical thrombin at Duke University Medical Center and summarize these cases in addition to 13 patients previously reported in the literature. In most cases, the inhibitor developed following a second (or subsequent) exposure to topical thrombin. The clinical course was extremely variable, ranging from totally asymptomatic to life‐threatening hemorrhage. The most consistent laboratory abnormality was a prolonged bovine thrombin clotting time, which corrected, at least partially, when human thrombin was substituted for bovine thrombin. Some of these patients also developed factor V inhibitors with prolonged prothrombin and activated partial thromboplastin times. Although these patients have prolonged clotting times, they should not be considered “autoanticoagulated,” since thromboembolic complications can still occur. Therapeutic intervention is largely empirical and depends on the clinical manifestations of the individual patient. © 1994 Wiley‐Liss, Inc.
Prevalence of abnormal iron studies in heterozygotes for hereditary hemochromatosis: An analysis of 255 heterozygotes
Authors: Adams Paul C.
Published: February 2007

Iron studies were compared in 434 patients from 80 hemochromatosis families classified as putative homozygotes, heterozygotes, and normal by HLA typing. There were 28 of 255 (11%) heterozygotes with an elevated serum ferritin and 22 of 255 (8.6%) with an elevated transferrin saturation. Serum ferritin (140 ± 10.2 μg/liter; mean ± standard error) was greater in heterozygotes than in normal subjects (87 ± 8.5 μg/liter; P < .05, Mann Whitney test). Transferrin saturation was greater in heterozygotes (38% ± 0.88%) than in normal patients (29% ± 1.1%; P < .0001). Mean hepatic iron concentration was 54 ± 6 μmol/g (n = 17), and the hepatic iron index was <2 in these patients. Most heterozygotes for hemochromatosis have a normal serum ferritin and transferrin saturation. Heterorygotes with minor elevations in serum ferritin or transferrin saturation do not have significant iron overload as assessed by hepatic iron concentration. © 1994 Wiley‐Liss, Inc.
Skin manifestation of agnogenic myeloid metaplasia
Authors: Loewy Gabriel , Mathew Anna , Distenfeld Ariel
Published: February 2007

Agnogenic myeloid metaplasia (AMN) with myelofibrosis is a clonal malignancy of the hematopoletic stem cell. The disease is characterized by increased endothelial cell and fibroblast proliferation, resulting in increased deposition of fibronectin, laminin, and collagen in the bone marrow. In advanced disease, extramedullary hematopoiesis (EMH) is invariably seen in the spleen and liver. The lymph nodes are also frequent sites of EMH, but other organs, especially the kidneys, arenals, lungs, pleura, ovaries, gastrointestinal tract, and dura, may also be involved. Skin manifestations are rare. They may present in several ways: erythematous plaques, nodules, diffuse or papular erythema, ulcers, and bullae. Histopathology of these lesions reveals cells from one or more myeloid lineage in the dermis, erythrold, or megakaryocytic series alone or in combination. In rare cases, all three cell lines are demonstrated. © 1994 Wiley‐Liss, Inc.
Treatment of refractory undifferentiated acute myelogenous leukemia with all‐trans‐retinoic acid
Authors: Griggs Jennifer J. , Henley Susan E. , Rowe Jacob M.
Published: February 2007

A patient is described with undifferentiated acute myeloblastic leukemia refractory to two courses of daunorubicin and cytosine arabinoside. Because some the myeloblasts developed morphologic features of promyelocytes, the patient was treated with all‐trans‐retinoic acid (ATRA) in an attempt to promote maturation. Cytogenetic studies and sensitive molecular analysis did not reveal any abnormality classically associated with acute promyelocytic leukemia. Serial bone marrow biopsies demonstrated myeloid maturation, and the patient uneventfully went into a sustained complete remission. A review of the literature confirms this to be an apparently hitherto undescribed response to ATRA that may have therapeutic implications in similar patients. © 1994 Wiley‐Liss, Inc.
Molecular abnormality of a unique japanese glucose‐6‐phosphate dehydrogenase variant (G6PD Kobe) with a greatly increased affinity for galactose‐6‐phosphate
Authors: Hirono Akira , Nakayama Shiro , Fujii Hisaichi , Miwa Shiro
Published: February 2007

Systematic molecular analysis of a Japanese class 1 glucose‐6‐phosphate dehydrogenase (GGPD) variant (G6PD Kobe) cONA revealed a unique nucleotide substitution (1318 C to T) in exon 11, which predicts a substitution of leucine for phenylalanine at residue 440. This substitution is located in a region surrounding the putative structural NADP‐binding domain. The markedly abnormal kinetics of glucose‐6‐phosphate (GGP) of GGPD Kobe suggest the interaction between both NADP and G6P binding sites. © 1994 Wiley‐Liss, Inc.
A possible survival advantage in adults with acute leukemia receiving ABO‐identical platelet transfusions
Authors: Heal Joanna Mary , Kenmotsu Naomi , Rowe Jacob M. , Blumberg Neil
Published: February 2007

In a small cohort of leukemic patients participating in a randomized trial of ABO‐identical vs. ABO‐unmatched platelet transfusions, a statistically significant decrease in remission duration and increase in mortality were observed in patients receiving ABO‐unmatched platelet transfusions. This difference was unexplained by previously described prognostic factors for remission duration and survival. Further study of this association is warranted. © 1994 Wiley‐Liss, Inc.
von Willebrand's disease: Use of collagen binding assay provides potential improvement to laboratory monitoring of desmopressin (DDAVP) therapy
Authors: Favaloro Emmanuel J. , Dean Mark , Grispo Linda , Exner Tom , Koutts Jerry
Published: February 2007

This report describes studies investigating the use of a collagen binding assay to improve the laboratory monitoring of desmopressin (DDAVP) therapy in patients with von Willebrand's disease (vWD). We evaluated the response of seven patients with vWD (four type I, three type IIA) to DDAVP, administered using a standard protocol, by assessing levels of von Willebrand factor (vWF) and factor VIII, as well as performing skin bleeding times (SBT) prior to, and at sequential time points following, DDAVP administration. The study employed the following assays: von Willebrand factor antigen assay (vWF:Ag; determined by ELISA); a novel functionally based collagen binding assay (CBA; determined by ELISA); ristocetin cofactor assay (RCof; determined by platelet aggregometry); von Willebrand factor muitimer analysis (using SDS‐agarose gels); factor VIII coagulant (FVIIIC; determined by clotting assay); and factor VIII antigen (FVIIICAG; determined by ELISA). All patients showed an initial incremental increase in vWF/FVIII levels using all assays above, and some showed some correction in SBT. Although the absolute levels of vWF/FVIII antigen or activity varied between patients, the CBA was found to provide consistently the greatest proportional incremental increases (i.e., ‐fold) compared to baseline (pre‐ DDAVP) levels. Accordingly, we consistently observed an increase in the CBA to vWF:Ag ratio for all patients evaluated. This supplements previous findings that have suggested a unique ability of our CBA procedure to bind preferentially to higher molecular weight (i.e., more functionaily active) forms of vWF. We therefore propose that the use of the above test combination (e.g., vWF:Ag plus CBA) may provide the basis for more accurate estimation of a patient's functional responsiveness to DDAVP therapy in future studies. © 1994 Wiley‐Liss, Inc.
Stability of factor VIII concentrates after reconstitution
Authors: Schulman Sam , Gitel Sanford , Martinowitz Uri
Published: February 2007

Adjusted‐dose continuous infusion of factor VIII (FVIII) has recently been shown to reduce the doses of the factor in patients undergoing surgery by 50‐75%. The main limitation of this method has been the instability of factor concentrates. All manufacturers are recommending infusion of the concentrate within hours after reconstitution. We studied the stability of 15 different lyophillzed F VIII products. Reconstituted samples were stored for periods of 4, 24, and 72 hr and 1, 2, 3, and 4 weeks at temperatures of WC, 20‐23°C, and 37°C in their original glass containers and in plastic tubes and then frozen. Assays were performed in duplicate, using a one‐stage clotting method and a chromoge nlc assay for F VIII, wlth all samples from a single concentrate In the same run. Activation of the coagulation factor occurred In some concentrates, more often at 44°C than at 20‐23°C or 3PC. The stability of all products was substantially better than that declared by the manufacturers. Several concentrates maintained factor activities above 80% of baseline for the entlre period of 4 weeks at 44°C or at 20‐23°C. The results demonstrate that many of the F VIII concentrates may be used for continuous infusion. © 1994 Wiley‐Liss, Inc.
α‐Interferon treatment for idiopathic hypereosinophilic syndrome
Authors: Bockenstedt Paula L. , Santinga John T. , Bolling Steven F.
Published: February 2007

Idiopathic hypereosinophilic syndrome (HES) is a poorly understood disorder characterized by a markedly elevated peripheral blood eosinophil count in the absence of known associated causes of hypereosinophilia. Idiopathic hypereosinophilic syndrome is associated with eosinophil‐induced organ damage, including endomyocardial and pulmonary fibrosis, stroke, and gastrointestinal disease. Treatment of idiopathic HES is centered on the reduction of peripheral circulating eosinophils in an effort to diminish tissue infiltration and destruction. Multiple cytotoxic agents have been tried, with variable resutts. Prednisone and hydroxyurea have remained the therapies of choice in long term treatment of idiopathic HES. We report here the successful 2 year treatment of aggressive idiopathic HES, refractory to hyroxyurea and prednisone, with α‐interferon. © 1994 Wiley‐Liss, Inc.
Hereditary hemochromatosis and red cell aplasia
Authors: Adams Paul C.
Published: February 2007

A 63‐year‐old white man with myasthenia gravis and red cell aplasia was found to have hepatic iron overload. The differential diagnosis included hereditary hemochromatosis and secondary iron overload related to red cell aplasia. Family studies of siblings, including HLA typing, initially suggested a diagnosis of secondary iron overload. The investigation of a remote sibling led to the final diagnosis of hereditary hemochromatosis. The case illustrates the importance of complete family investigations in the differentiation between hereditary hemochromatosis and secondary iron overload and the potential hazard of using HLA typing as an indirect genetic test for hereditary hemochromatosis. © 1994 Wiley‐Liss, Inc.
Intravenous extended infusion of recombinant human soluble thrombomodulin prevented tissue factor‐induced disseminated intravascular coagulation in rats
Authors: Mohri Mitsunobu , Oka Michiko , Aoki Yoshikazu , Gonda Yasunori , Hirata Sigeto , Gomi Komakazu , Kiyota Takao , Sugihara Taisuke , Yamamoto Shuji , Ishida Torao , Maruyama Ikuro
Published: February 2007

This study demonstrated that intravenous infusion of recombinant human soluble thrombomodulin (rhs‐TM) could Inhibit disseminated Intravascuiar coagulation (DIC) caused by 4 hr infusion of tissue factor (TF) in rats. Extended infusion of TF reduced fibrinogen and platelet counts and elevated serum FDP level. Pretreatment and coinfusion of rhs‐TM could block changes of these DIC‐parameters without prolongation of APTT. Heparin, which is a potent anti‐DIC drug, could also inhibit these changes with extra prolongation of APTT and PT. Thus, these results suggest thrombomodulin prevent DIC less bleeding tendency than heparin. © 1994 Wiley‐Liss, Inc.
Prevalence of antithrombin deficiency in healthy blood donors: A cross‐sectional study
Authors: Wells Philip S. , Blajchman Morris A. , Henderson Penny , Wells Michael J. , Demers Christine , Bourque Ron , McAvoy Ann
Published: February 2007

The prevalence of antithrombin (AT) deficiency In the general population has been variously estimated to be between 0.05 and 5 per 1,000 in the population; 2,491 blood donors were screened In an attempt to clarify this Issue using plasma samples taken from the blood donor units. From this initial population, 122 individuals were identified as having plasma AT levels lower than 2 standard deviations below the normal mean. Twenty‐two samples had evidence that thrombin had been generated during blood collection and the remaining cohort of 100 blood donors were asked to return but only 59 complied. The data obtained from these 59 were compared with that from 51 age‐ and sex‐matched control blood donors. Both groups of subjects were assessed for previous evidence, or family history, of thrombotic events, as well as exposure to risk factors associated with the development of deep vein thrombosis (DVT). All had venous blood samples taken from which the supernatant plasma was Immediately removed and quick frozen for later assaying. Only 6 of the 59 subjects with initial low AT levels had repeat AT‐Xa levels below 0.80 units/ml (normal range 0.94 ± 0.14). Upon repeating the AT‐Xa determinations on new samples from these six Individuals, only three were found again to be low. One was found to have a type 3 AT deficiency (an Arg47Cys substitution). The other two with a low AT level had mean functional AT‐Xa levels of 0.61 and 0.71 units/ml, respectlvely, with correspondingly low AT:Ag levels consistent with a type 1 AT deficiency. Two of these three subjects has been in high risk situations without evidence of having developed DVT and none had evidence of venous reflux on Doppler venography. In addition, none had personal or family histories of previous thrombotic events. These present data Indicate that the prevalence of AT deficiency In our blood donor population is 2 per 1,000 (95% confidence intervals: 0.7‐6/1,000). © 1994 Wiley‐Liss, Inc.
Two different mutations in codon 68 are observed in Hb G‐Philadelphia heterozygotes
Authors: Molchanova T. P. , Pobedimskaya D. D. , Ye Z. , Huisman T. H. J.
Published: February 2007

Through sequencing of amplified DNA containing the appropriate α‐giobin genes we have identified the base substitution leading to the formation of Hb G‐Philadelphia [α6B(El7)Asn Lys]. Three subjects (∼25% Hb G) had an AAC AAA change at codon 68 of the α2‐globin gene; the chromosome with this mutation carried two α genes (αα). Six subjects (∼33% Hb G) had an AAC AAG change at the same codon of the α2α1 hybrid gene on a chromosome with the 3.7 kb deletion (‐α3.7). These results indicate two inde pendent mutations which likely occurred in different populations; Increase In the level of Hb G is primarily dependent upon the loss of one or more α‐globin genes. © 1994 Wiley‐Liss, Inc.
CD34 immunohistochemistry of bone marrow biopsies: Prognostic significance in primary myelodysplastic syndromes
Authors: Soligo Davide A. , Oriani Alessandro , Annaloro Claudio , Cortelezzi Agostino , Calori Rossella , Pozzoli Ermanno , Nosella Diego , Orazi Attilio , Deliliers Giorgio Lambertenghi
Published: February 2007

Bone marrow (BM) biopsies from 58 patients with primary myelodysplastic syndrome (MDS) were studied using QBEND10, a monocional antibody that recognizes the human progenitor CD34 antigen in routine aldehyde‐fixed paraffin‐embedded samples. FAB subtypes were RA (5 patients), RARS (9 patients), RAEB (20 patients), RAEBt (11 patients), CMML (3 patients). In addition, 10 MDS patients whose BM biopsies revealed heavy reticulum fibrosis were included. Neither the percentage of CD34+ cells nor the number of CD34+ aggregates (defined as clusters of 3 or more cells) correlated with the presence and morphology of abnormal localizations of immature precursors (ALIP). When all patients were considered, median survival was 69 months in those with less, and 25 months in patients with more than 1% CD34+ cells (P < 0.05). Median survival was 15 months in patients with CD34+ aggregates and 41 months in those without aggregates (P = 0.0017). When RAEB patients were considered median survival was 41 months in those with less than 1%, and 29 months in those with more than 1% CD34+ cells; the 4‐year survival chance was 45% in the former and 18.3% in the latter group. Therefore, CD34 positivity of more than 1% identifies a subset of RAEB patients with shorter life expectancy. In addition, leukemic transformation was observed in 11 of 35 patients (31%) with no CD34 aggregates, but in 14 of 23 patients (60%) with aggregates (P < 0.05). CD34 immunostaining, which can be easily performed on routinely prepared BM biopsies, was found to be a powerful prognostic tool for predicting survival and outcome in MDS. © 1994 Wiley‐Liss, Inc.
Pure red cell aplasia associated with angioimmunoblastic lymphadenopathy with dysproteinemia
Authors: Lynch James W. , Elfenbein Gerald J. , Noyes Ward D. , Braylan Raul C. , Gross Mary Ann , Weiner Roy S.
Published: February 2007

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) can best be described as a disorder of T‐cells resulting in amplification of the B‐cell response and clinical symptoms of lymphadenopathy, fever, hepatosplenomegaly, and a variety of blood abnormalities. Pure red cell aplasia (PRCA), an autoimmune disorder resulting in selective aplasia of the erythroid series, has only rarely been associated with AILD. Herein we report three cases of AILD and PRCA. Serum from one patient was available for study and contained a dose‐dependent inhibitor of the CFU‐E but not CFU‐GM cultures from normal bone marrow. This activity was found in the globulin fraction after ammonium sulfate precipitation. Patients with AILD are known to make antibodies to many autologous epitopes, and the most well‐characterized mechanism of PRCA involves antibodies to red cell precursors. Our serum data are consistent with the hypothesis that such an antibody existed in our patient. Aggressive treatment of these patients resulted in transient improvement in two; however, all three died without achieving a durable complete remission with two dying of infectious complications. © 1994 Wiley‐Liss, Inc.
Genotype of subjects with borderline hemoglobin A2 levels: Implication for, β‐thalassemia carrier screening
Authors: Galanello R. , Barella S. , Ideo A. , Gasperini D. , Rosatelli C. , Paderi L. , Paglietti E. , Sollaino C. , Perseu L. , Loi D. , Cao A.
Published: February 2007

In this study, we have defined by molecular analysis, the α, β, and δ globin genotype in a group of individuals with normal or thal‐like red cell indices but borderline hemoglobin (Hb)A2 levels, who were identified in a program for β‐thal carrier screening. In 37 of 125 individuals with borderline HbA2 levels, we detected a molecular defect in the β, in both the δ and the β, or in the α globin gene. Specifically seven of these subjects were carriers of the −101 C T mutation, ten of the IVSI nt6 T C mutation, 16 were double heterozygotes for δ and β thal, and two had the triple α globin gene and two the single α globin gene deletion. From these results, we may conclude that subjects with borderline HbA2, particularly when they marry a typical β‐thal carrier, should be extensively investigated in order not to miss heterozygous β‐thalassemia. © 1994 Wiley‐Liss, Inc.
Anticoagulation with anisindione in patients who are intolerant of warfarin
Authors: Grosset Alan B. M. , Allen Jill E. , Rodgers George M.
Published: February 2007

Patients who require oral anticoagulation usually receive warfarin. We used an indanedione drug, anisindione, in two patients who were intolerant of warfarin but who needed long‐term oral anticoagulation. The use of this alternative oral anticoagulant is reviewed. © 1994 Wiley‐Liss, Inc.