Effect of the evaluation parameter on sensitivity of resonance thrombography of thrombocytopenia in dogs

Based on 109 blood samples taken from 36 dogs suffering from thrombocytopenia resonance thrombography with the resonance thrombograph RTG 801 (von Hoerner und Sulger Electronic GmbH, Schwetzingen; manufacturer: Fresenius AG, Bad Homburg) was distinctly more sensitive and more closely correlated to the platelet count using an optimized parameter of the resonance thrombogramm (RTG) in comparison to usual parameters. Nevertheless, clinical requirements regarding samples with platelet counts > 25,000/microliter were not fulfilled. Out of 13 samples with reduced platelet count and simultanous extended capillary bleeding time, depending on the used parameter a maximum of 9 samples could be detected as pathological by the RTG. The normal RTG in part of the cases with clearly altered primary haemostasis contrasts to the exclusive use of RTG in the screening of thrombocytopenia in dogs.     

2-CDA in treatment of hairy cell leukemia: a comparison between intravenous and subcutaneous administration. Swiss Study Group of Applied Cancer Research

2-chlorodeoxyadenosine (2-CDA) is very effective in the treatment of patients with hairy-cell leukaemia, with an overall response rate of 80-95%. The standard treatment is a continuous intravenous infusion for 7 days. The bioavailability of 2-CDA after subcutaneous injection is 100%, but the concentration-time profile is completely different compared to continuous intravenous administration. In the present study we compared the intravenous standard treatment (group 1, n = 22; 0.1 mg/kg/d for 7 days, civ.) with subcutaneous administration of 2-CDA (group 2, n = 62; 0.14 mg/kg/d for 5 days, s.c.) in patients with hairy-cell leukaemia. In group 1, 96% (21/22) of patients responded to 2-CDA (complete remission 73%, partial remission 23%) and in the second group 97% were responsive (complete response 76%, 47/62; partial remission 21%, 13/62). The percentage for moderate and severe infections in the trial with intravenous and subcutaneous treatment was 14% and 26% respectively (p = 0.37). We conclude that subcutaneous administration of 2-CDA in patients with hairy-cell leukaemia is feasible and economical and results in comparable responses and toxicity compared to the intravenous standard treatment.     

Effect of YM294, recombinant human interleukin-11, on carboplatin-induced thrombocytopenia in rats

We investigated the effects of YM294, recombinant human interleukin-11, on changes in blood cell levels in carboplatin-treated rats. Continuous infusion of YM294 was carried out by either intravenous or subcutaneous injection (10 and 100 micrograms/rat/day) for 14 days via an implanted osmotic pump. Carboplatin (30 mg/kg iv) significantly decreased platelet counts on days 7-9; counts subsequently increased to levels greater than the initial level by day 21. Intravenous administration of YM294 inhibited this decrease in platelet count by carboplatin and increased the platelet count in the recovery phase in a dose-dependent manner. YM294 also showed effects on carboplatin-induced changes in white blood cell and red blood cell counts; these effects seemed, however, to be neither consistent nor dose-dependent. The effects of YM294 on subcutaneous infusion were similar to those on intravenous infusion. The effect of YM294 on the survival of rats treated with a higher dose of carboplatin (60 mg/kg iv) was also investigated. YM294 (100 micrograms/rat/day) given by continuous intravenous infusion increased the 30-day survival rate. These results confirm the utility of YM294 in the treatment of thrombocytopenia after chemotherapy.     

2-Chlorodeoxyadenosine treatment after splenectomy in patients who have myelofibrosis with myeloid metaplasia

2-Chlorodeoxyadenosine (2-CdA) is a purine nucleoside analogue with therapeutic activity in low-grade lymphoproliferative disorders. In addition, 2-CdA has a potent myelosuppressive effect, and it has been shown to be toxic to malignant myeloid cells both in vitro and in vivo. In this pilot study we treated nine patients who had advanced myelofibrosis with myeloid metaplasia (MMM) and progressive hepatomegaly or symptomatic thrombocytosis after therapeutic splenectomy. 2-CdA was administered at 0.05-0.1 mg/kg/d for 7 d for one to five treatment cycles. A reduction in liver size associated with marked improvement in fatigue and control of thrombocytosis and leucocytosis was achieved in seven of the nine patients (78% response rate). In four of the seven responding patients the reduction in liver size was durable (4-28 months) and was associated with a decrease in serum alkaline phosphatase levels. However, no patient had improvement in anaemia, and two of the seven initially responding patients have since died of acute leukaemia or progressive disease. Improvement in bone marrow fibrosis was noted in two of five available post-treatment marrow examinations. Toxicity was mainly myelosuppression, which was severe in two patients. 2-CdA may be considered a palliative therapeutic agent after splenectomy in noncytopenic patients with MMM who have progressive hepatomegaly or extreme thrombocytosis.     

Effect of splenectomy on HIV-related thrombocytopenia and progression of HIV infection in patients with severe haemophilia

Between May 1983 and September 1991 eleven patients with severe haemophilia underwent splenectomy for HIV-related thrombocytopenia. The sustained complete remission rate (platelets > 100 x 10(9)/l) was 82% over a mean follow-up period of 54 months. The group was compared with 22 age-matched non-thrombocytopenic HIV seropositive haemophiliacs who had not undergone splenectomy. Both groups had equivalent use of factor concentrate and there was no significant difference between the groups in terms of anti-retroviral treatment. Analysis of clinical progression of HIV infection and CD4 positive lymphocyte (CD4+) counts, for the time since splenectomy, revealed no significant difference in progression of HIV infection in the splenectomized group compared with the control group. It is concluded that splenectomy is an effective treatment for HIV-related thrombocytopenia and has no adverse effect on the progression of HIV infection.     

Prognosis of myeloid metaplasia with myelofibrosis

The study of the evolution of 168 cases of idiopathic myeloid splenomegaly allowed to point out the prognostic value of the clinical hematologic, isotopic and radiological parameters. The correlation of these data with the histological type of the osteomedullary lesions at the time of the diagnosis, allows to confirm the long survival of the hyperplastic formes (type I) and the more reserved prognosis in advanced myelofibrosis (type II and III together). Indeed, median survival is of 82 months for type I, and 60 months for type II and type III together. It seems advice to gather the two last types and so, to compare two anatomoclinical entities : one is characterized by hyperplastic marrow with reticulinic fibrosis, usually associated with enlarged spleen and sometimes even with increase red blood cells volume but without radiological bone lesions; the other one is characterized by a marrow of middle importance or marked marrow depletion, fibrosis, with or not osteosclerosis, and shows moderate or marked radiological lesions (respectively 16,9% of the cases) and, often, pancytopenia.     

Splenunculectomy in recurrent thrombocytopenia

A 13-year-old boy developed thrombocytopenic purpura in 1953 which improved during 4 weeks of cortisone therapy. Following 13 years of intermittent symptoms the platelet count was found to be 8,000/mul. After splenectomy the patient was asymptomatic for 8 years, but had a recurrence of symptoms and thrombocytopenia in 1974. An initial spleen scan with 99Tcm sulfur colloid was negative; but when repeated with a gamma-camera and shielded liver, a splenunculus was demonstrated. After splenunculectomy a rapid remission occurred, and the patient has been well for 13 months.     

Occurrence of myelofibrosis in individual types of chronic myeloproliferative diseases

BACKGROUND: During the course of chronic myeloproliferative disorders (CMPD), myelofibrosis (MF) represents a negative prognostic factor. The data concerning the incidence and progression of MF are rather heterogenous. OBJECTIVES: The aim of the study was to evaluate the incidence and progression of MF in cases of CMPD registered in the Consultation Center for Haematopathology Biopsies in Martin Faculty Hospital. METHODS: Fibrotic changes involving bone marrow were evaluated histologically semiquantitatively using reticulin fiber impregnation (method of Gomori). The study included 77 cases of chronic myelocytic leukemia (CML), 99 cases of polycythaemia vera (PV), 38 cases of essential thrombocythaemia (ET), and 126 cases of the fourth type of CMPD, mostly known as myelofibrosis/osteomyelofibrosis type (MF/OMF). The occurrence and degree of MF were evaluated at the time of all primary biopsies; in 52 of cases also in rebiopsy material. RESULTS: At the time of primary diagnosis, MF occurred in 37/77 (48%) cases of CML, in 27/99 (27.3%) cases of PV, in 8/38 (21%) cases of ET, and in 119/126 (94.4%) cases of MF/OMF. In repeated (secondary) biopsies, the progression of MF or evolution to MF was most common in CML and MF/OMF types. CONCLUSIONS: At the time of the CMPD diagnosis, more than 50% of cases showed the presence of MF. During the course of CMPD, the MF seems to represent a dynamic process evolving the underlying disease. The early diagnosis of MF is important for the selection of the appropriate therapeutic regimen. (Tab. 3, Fig. 2, Ref. 23.)     

Quantitative studies of splenic erythropoiesis in polycythaemia vera and myelofibrosis

A quantitative scanning method employing cyclotron-produced 52Fe has been developed to assess splenic erythropoiesis in patients with myeloproliferative disorders. In 12 patients with myelofibrosis splenic uptake of 52Fe was from 5.0% to 48% of the injected dose. Although a single patient with classical polycythaemia vera had a minor uptake of 2.8% of six other patients with this diagnosis showed no concentration of isotope in the splenic area. The fraction of 52Fe in the spleen of four patients with 'transitional' myeloproliferative disorders characterized by a high red cell mass, hypercellular bone marrow and a leucoerythroblastic blood film varied from 5% to 41%. No clear relationship was noted between the degree of splenic erythropoiesis as defined by this technique and the level of haemoglobin, the degree of splenomegaly, the effectiveness of erythropoiesis of traditional 59Fe surface counting. If splenectomy is considered in patients with myelofibrosis splenic 52Fe quantitation will provide more precise data on the contribution of splenic erythropoiesis than 59Fe surface counting alone.     

A biological study on the efficacy of low-dose subcutaneous interleukin-2 plus melatonin in the treatment of cancer-related thrombocytopenia

The production of cytokines involved in platelet generation, including interleukin (IL)-3, IL-6 and IL-11, is stimulated by IL-2. However, the platelet number has been shown to decrease on IL-2 cancer therapy, and this side effect depends on the enhanced peripheral platelet destruction following the activation of the macrophage system by IL-2 itself. Our previous studies showed that IL-2-induced macrophage activation may be counteracted by the pineal hormone melatonin (MLT). On this basis, a pilot study with IL-2 plus MLT was performed to evaluate its influence on the platelet number in cancer patients with persistent thrombocytopenia. The study included 20 advanced solid tumor patients, who received IL-2 at 3 million IU/day s.c. for 6 days/week for 4 weeks in association with MLT (40 mg/day orally). A normalization of the platelet number was achieved in 14/20 (70%) patients. This pilot study shows that the therapy with low-dose IL-2 plus MLT, in addition to its previously described antitumor activity, may also be effective in the treatment of cancer-related thrombocytopenia.     

Successful treatment of early secondary myelofibrosis in SLE with IVIG

With increasing demand for esthetics, dentists face the challenge of delivering definitive restorations that fulfill patients' expectations of esthetics, biocompatibility, and durability. Recent technical developments have encouraged fabrication of gold-reinforced porcelain inlays that meet these important criteria. This article describes a sequence to construct metal-reinforced porcelain inlay restorations.     

Relationships between severe neonatal thrombocytopenia and maternal characteristics in pregnancies associated with autoimmune thrombocytopenia

A molecular method for the identification of ectomycorrhizae belonging to five species of white truffle is described. The polymerase chain reaction (PCR) and universal primers were used to amplify internal transcribed spacers and 5.8S rDNA, target sequences present in a high number of copies. The amplified products were digested with restriction enzymes in order to detect interspecific polymorphisms. Species-specific restriction fragment length polymorphism patterns were determined for all five species. The use of PCR in conjunction with restriction enzymes provides a sensitive and efficient tool for use in distinguishing ectomycorrhizal species and monitoring inoculated seedlings or field mycorrhizal populations.     

Immune thrombocytopenia in children: the immune character of destructive thrombocytopenia and the treatment of bleeding

It is now recognized that different forms of destructive thrombocytopenia due to antibody binding to platelets exist, which can be differentiated by sensitive new assays. Thus, the name has been changed from idiopathic to immune thrombocytopenic purpura (ITP). The immune character of ITP has been further supported by the success of treatment with human antibody concentrate-immunoglobulin treatment. During different studies of ITP in children, it has been recognized that only patients with bleeding in addition to a platelet count less than 20 x 10(9)/L need to be treated. The various forms of treatment are reviewed.     

Cladribine (2-CDA) given as subcutaneous bolus injections is active in pretreated Waldenstr?m's macroglobulinaemia. Swiss Group for Clinical Cancer Research (SAKK)

Clinical trials with intravenous cladribine infusions in pretreated patients with Waldenstr?m's macroglobulinaemia have shown a response rate of 40%. Our pharmacokinetic studies revealed that the bioavailability of subcutaneous cladribine is complete but that the concentration-time profile is very different from intravenous administration. We designed this phase II multi-institutional trial to study the activity and toxicity of cladribine given as s.c. bolus injections in patients with symptomatic Waldenstr?m's macroglobulinaemia. Between May 1993 and October 1995, 25 patients were accrued: male/female 18/7, median age 65 years (range 44-85). All except one patient had been pretreated with more than one regimen (median 2, range 0-10). 18 patients had progressed under previous therapy and six were in relapse. All patients received cladribine for a total dose of 0.5 mg/kg per cycle as s.c. bolus injections divided over 5 d at > or = 4 week intervals, for a maximum of six cycles. All 25 patients were evaluable for toxicity and response. A total of 67 cycles were administered (median 3 cycles, range 1-6). Overall response rate including disease stabilization which had been progressive under previous therapy was 68%. 10 patients (40%, 95% CI 21-61%) achieved a partial remission. Seven responders had been progressive under previous therapy. Maximum responses were reached no later than the third cycle. Median time to treatment failure and remission duration were 4.4 (range 0.5-33) and 8 months (5-29), respectively. Four patients (16%) suffered from infections W.H.O. grade > or = 2 (pneumonia grade 2, Staphylococcus septicaemia grade 3, viral encephalitis and pneumonia, both grade 4 with complete resolution). No other severe adverse events were observed. Cladribine given as s.c. 5 d bolus injections was found to be active in pretreated Waldenstr?m's macroglobulinaemia and resulted in durable remissions.     

Ischemic therapy in thrombocytopenia from hypersplenism

Percutaneous transfemoral arterial balloon occlusion or gelatin sponge embolization of the splenic artery or both were carried out in three high-risk patients with hepatic cirrhosis to reduce splenic hyperfunction and improve severe thrombocytopenia. Although this maneuver raised peripheral platelet counts in each patient, in one patient left upper quadrant pain with splinting of the lower chest cage led to hypostatic lower lobe pneumonia, while in another septic splentitis with gas-forming organisms necessitated splecectomy. Transfemoral occlusion of the splenic artery, although an effective, noninvasive approach to control splenic hyperfunction, has at the same time potential dangers that should be viewed with extreme caution in therapeutic application.     

The role of transforming growth factor-beta in PEG-rHuMGDF-induced reversible myelofibrosis in rats

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) injected at a suprapharmacologic dose (100 microg/kg) daily for 5 d in normal rats caused marked increases in marrow megakaryocytes and platelet counts at 6-8 d followed by gradual decreases to control levels at 10-20 d. Interestingly, in addition to the expected thrombopoiesis, PEG-rHuMGDF was associated with myelofibrosis with a predominance of reticulin fibres at day 10 followed by complete normalization by day 20. At 6-8 d, the levels of transforming growth factor-beta1 (TGF-beta1) in the extracellular fluid of the marrow, the platelet poor plasma, and the platelet extract were increased 23-, 7- and 2-fold, respectively. The elevated levels of TGF-beta1 were gradually reduced to baseline levels at 13-20 d in accordance with the normalization of myelofibrosis and thrombopoiesis. An ultrastructural analysis showed that large fragments of megakaryocytes were deposited in the marrow parenchyma of PEG-rHuMGDF-treated rats at day 6. PEG-rHuMGDF administration at pharmacologic doses (1 and 10 microg/kg) did not induce the deposition of reticulin fibres in the marrow. These findings suggest that TGF-beta1 leaked from megakaryocytes is involved in the development of the PEG-rHuMGDF-induced myelofibrosis and that this is a reversible process related to the regulation of the excess production of platelets.     

Essential thrombocythemia in transformation to smouldering megakaryoblastic leukemia with myelofibrosis

Leukemic transformation in essential thrombocythemia (ET) is rare. We describe a patient with ET which transformed to megakaryoblastic leukemia with myelofibrosis after treatment with melphalan for 8 years. His course after transformation smouldered for 20 months without antileukemic chemotherapy. A 61-year-old man was referred by a local doctor to Niigata University Hospital due to nasal bleeding in June 1984. Complete blood count (CBC) was as follows; hemoglobin 12.4 g/dl, platelets 268.8 x 10(4)/microliters, and white blood cells 11,900/microliters, with differentials of 39% PMN, 1% basophils, 2% eosinophils, 4% monocytes, and 13% lymphocytes. Bone marrow examination revealed hyperplasia of megakaryocytes without increase of reticulin fibers. Neutrophil alkaline phosphatase activity and karyotype of marrow cells were normal. ET was diagnosed. He was followed up by local doctor. The platelet count was controlled at a level of approximately 40 x 10(4)/microliters with melphalan for eight years. In January 1992 he developed pain in his lower extremities. He was admitted to our hospital on May 29, 1992. CBC was as follows; hemoglobin 8.9 g/dl, platelets 14.3 x 10(4)/microliters, and white blood cells 3,500/microliters, with differentials of 25% PMN, 5% monocytes, 28% lymphocytes, and 24% blasts. Bone marrow aspiration was unsuccessful and bone marrow biopsy revealed increases in fibroblasts and collagen fibers. Circulating blasts were positive for CD4, CD7, CD25, CD13, CD33, CD34, and HLA-DR and partly positive for CD41 and CD36. In ultrastructural cytochemistry blasts were positive for platelet peroxidase but negative for myeloperoxidase. Cytogenetic study revealed 46, XY, +der (1) t(1:7) (p11;q11) in all of five metaphases. He was diagnosed with megakaryoblastic leukemia accompanied by myelofibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of thrombocytopenia on the activated coagulation time

Cortical efferents grow from deep cortical layers to innervate numerous subcortical structures late in embryogenesis. The mechanisms that control their development are poorly understood. We co-cultured organotypic embryonic cortical explants with other tissues, maintaining a distance between them to avoid contact-mediated interactions. At embryonic day 15, when the cortical plate comprises only cells of the deep cortical layers, outgrowth from cultured cortex was stimulated by co-cultured subcortical structures, but not by additional cortex or liver. These data support the hypothesis that diffusible factors from subcortical structures, and not from the cortex itself, enhance cortical efferent growth.