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[Treatment of disseminated oro-pharyngo-laryngeal epidermoid carcinomas with a combination of methotrexate and bleomycine in small doses].

In the previously published series of patients with generalized head and neck epidermoid carcinoma, a high dose combination of methotrexate (MTX) (0.4 mg/kg biw. i.v.) and bleomycin (BLM) (30 mg biw. iv) produced an objective remission rate of 60% with a median duration of 9 weeks. The disappointingly short duration of the remissions was tentatively related to the short period of treatment, which was limited to 5 weeks in order to keep the cumulative dosage of BLM below 300 mg. In the present study, covering 26 patients, a lower weekly dose was adopted (BLM 15 mg, MTX 0.6 mg/kg). 13 partial remissions were obtained with a median duration of 26 weeks; in 7 cases there was no evolution, in 6 cases progression of the tumor was registered, and there was one death from hematological toxicity. The major toxicity was leuko- and thrombopenia with one toxic death. Digestive and cutaneous side effects and fever were minor. There were 2 cases of major pulmonary toxicity, one of which was lethal. In conclusion, a combination of MTX and BLM at a relatively low dosage is active in disseminated head and neck carcinoma and appears to be compatible with longer maintenance of palliation in comparison with results obtained at a high dose level.

Bleomycin↗

[Lymphocytotoxic antibodies in malaria].

We applied the microlymphocytotoxicity method to the detection of lymphocytotoxic antibodies in case of 37 patients with acute malaria or 61 patients who sojourned in endemic malaria area and presented antibodies against plasmodial antigens (indirect immunofluorescence test greater than or equal to 1/20). Lymphocytotoxic antibodies were found in 16 patients of the first group and their occurrence may explain the lymphopenia and to a lesser extent the neutropenia and thrombopenia observed in some cases. In the second group lymphocytotoxic antibodies were present in 9 cases. In all samples no anti-HLA specificity was evidenced. Four patients were submitted to auto-cross-match test and 3 were found positive suggesting that among these antibodies some are auto-antibodies with anti-lymphocyte specificity.

Antilymphocyte Serum↗

[Cooperative studies on surgical adjuvant immunochemotherapy for prevention of postoperative recurrence of gastric cancer].

A controlled clinical trial of surgical adjuvant immunochemotherapy of gastric cancer was started in July, 1974 involving twelve institutes (Chairman; T. Kondo) in Japan. Patients with gastric cancer undergone curative resection were eligible. These patients were divided into 3 groups; Group A, mitomycin C (MMC) + 5-fluorouracil (5-FU): Group B, MMC + 5-FU + PSK or MMC + 5-FU + OK-432; and Group C, surgery alone. Of 1412 patients accumulated up to December 1977, 848 cases were evaluable: Group A-264 cases, group B-290 and group C-294. Side effects such as leukopenia, thrombopenia, elevated GOT and GPT, albuminuria and digestive disorders, were observed in 54 cases (20.5%) of group A and in 59 cases (20.3%) of group B. The 3-year survival rates of total cases were 79.2% with group A, 77.0% with group B and 85.2% with group C. The 2-year survival rates of histological stage II cases were 93.4% with group A, 90.5% with group B and 80.7% with group C. The difference in survival rate between A and C (12.7%) was statistically significant (p less than 0.05). The efficacy was not related to the histological type of gastric cancer. Adjuvant immunochemotherapy using OK-432 was significantly effective on a 1-year survival rate of stage IV gastric cancer.

Adult↗

Susceptibility of volume stress in Colisa fasciatus.

Intraperitoneal injections of 0.6% NaC1, commonly used as injection vehicle, at 10 mul/g, but not at 5 mul/g. elicit significant (p less than .05) transitory erythropenia, leucopenia, and thrombopenia at selected post-injection time intervals in female Colisa fasciatus, a fresh water teleost. It is suggested that administration of large volumes of injection fluid per gram body weight of experimental animals should be avoided lest it might distort physiological parameters, particularly those relating to blood components, under study.

Animals↗

[Clinical experiences with high-dose methotrexate].

40 patients with various forms of malignant disease, who had already been subjected to conventional regimens of treatment, were treated between 1976 and 1981 at the Department of Chemotherapy, Vienna University, with high-dose methotrexate (MTX) as sole therapeutic agent. 18 patients received MTX in moderately high doses of 250 mg/m2 to 750 mg/m2 at 10-day intervals. 19 patients were treated with high doses of 5 to 15 g MTX at 10-day intervals. In 2 cases of severe malignant non-Hodgkin's lymphoma one patient received 2 X 1 g MTX with an interval of 19 days between doses and the other received a single dose of 5 g MTX by infusion. One patient with alveolar soft part cell sarcoma was given ultra-high therapy, with a cumulative dose of 205 g. None of the patients in the group given moderately high-dose MTX therapy, whereas three in the high-dose group had an objective remission. Objective remission was obtained neither in the two lymphoma patients nor in the ultra-high-dose treated case. Complications such as leucopenia and/or thrombopenia were found in 9%, reversible transaminase activity increases in 45%, as well as a decrease in creatinine clearance in 10% of the cases. Irreversible severe kidney insufficiency was found in none of the cases. One patient with lymphoma died as a result of severe toxic epidermiolysis with involvement of the gastrointestinal mucosa, whilst the other suffered from pulmonary complications in the form of the respiratory distress syndrome. On the basis of our experience the use of high-dose MTX therapy as an alternative method following trials of all conventional regimens is not recommended.

Female↗

Prevention of thrombocytic defects in the br/br rabbit with folic acid and vitamin B12: analogy with the T.A.R. syndrome in humans.

Brachydactylia in the rabbit results from in utero haemorrhages leading to necrosis and post-natal amputations. Foetal liver study on day 14 to 16 of gestation, the critical period for thrombosis, reveals abnormalities of haematopoietic tissue. We observe a rarefaction of erythropoietic tissue and a defect of the megakaryocytic series resulting in erythrocyte macrocytosis and thrombopenia. Vitamin treatment (Folic acid + vitamin B12) administered to pregnant females prevents the above disorders and lead to production of mature forms in all the haematopoietic series. The T.A.R. syndrome (thrombocytopenia with absent radii) in humans, presents similarities with the physiological and clinical description of the br/br rabbit. Consequently, our research concerning the br/br foetuses seems to be a model for the study of several types of brachydactylia in humans either due to a vitamin deficiency or not.

Animals↗

A case of porphyria cutanea tarda with hemangioma of the liver.

The clinical incidence of porphyria cutanea tarda is apparently less in Japan than in European countries and the U.S.A.. In the last 7 years, porphyria cutanea tarda was encountered in the dermatologic clinic of Tokai University Hospital at the rate of one in twelve thousand patients with various kinds of skin diseases. This case is the first case in our medical clinic at Tokai University Hospital in the past 7 years, among 2,456 cases of liver diseases in which laparoscopy with needle biopsy of the liver was performed. The physiopathological aspects remain obscure. Unexpectedly, a hemangioma was disclosed under laparoscopic observation but it was clear that the hemangioma had no significant relation to the thrombopenia-hemangioma syndrome in this case.

Adult↗

[Mediterranean boutonneuse fever. Apropos of 154 recent cases].

The Mediterranean spotted fever is always present in the south of France. The actual incidence is unknown. The disease appears in summer. The diagnostic is based on the association of fever, "black spot" and exanthema and/or a seroconversion. Indirect immunofluorescence is the most used technique. Some patients have severe complications: neurologic, cardiovascular, renal, thrombopenia. These cases look like Rocky Mountain Spotted Fever. The treatment is based on tetracycline.

Adolescent↗

[Evaluation of the performance of Coulter S+II].

The technical performances of the Coulter S+II counter was evaluated for lymphocyte counts and the data obtained were compared to those supplied by the ELT 800 analyzer to the results for manual and Hemalog D counting methods. We assessed accuracy of three types of information supplied by the S+II model in the following conditions: erythrocyte indices in anemia, white cell histograms in chronic myeloid leukemia, chronic lymphoid leukemia, acute leukemia and eosinophilia, and the reliability of the analyzer in showing the degree of thrombopenia and hyperthrombocytosis.

Anemia↗

[Phase-1 study of the tolerance for increasing doses of recombinant human alpha 2 interferon in patients with advanced cancer].

Thirteen patients with malignant tumors were entered into a phase I trial with recombinant DNA human alpha 2 interferon (IFN alpha 2). The patients were given I.M. escalating doses of IFN alpha 2 ranging from 1-10(6) to 200-10(6) IU with a 72 hours washout between injections. In the majority of the patients, subjective symptoms were noted: fever, headache, chills, nausea, myalgias. Asthenia, anorexia, drowsiness appeared after the highest doses and disappeared without any sequellae. Leucopenia and thrombopenia were seen in 11 out of 13 patients. Hepatocellular toxicity was observed in 9 cases. Cardiac and vascular functions were not impaired by IFN alpha 2. The pharmacokinetic studies showed a maximum serum concentration between 4 and 6 hours after injection and the peak value was directly proportional to the dose. No neutralizing INF alpha 2 serum factor was detected during the treatment. The peak value for serum beta 2 microglobulin occurred 48 hours after and the N.K. activity was variably modified by IFN alpha 2 injections. A major clinical response was observed in 1 case, a minor response in 3 cases and a stabilisation of the disease in 4 cases.

Adult↗

[Diagnosis of defibrination syndromes in infectious pathology].

Severe infections and particularly infectious shock are frequently accompanied by a varying degrees of disseminated intra-vascular coagulation (DIC). The mechanism at work is complex, involving endotoxin or bacterial lipopolysaccharide constituents that damage vascular endothelium and activate intrinsic coagulation, platelet function and the release of leucocyte coagulation-promoting compounds. The activation of coagulation in turn activates prekallikrein and complement and plays a part in shock. The laboratory plays an essential role in diagnosing DIC, determining its repercussions on the parameters of haemostasis and in monitoring its course under antibiotics, which in some cases may be combined with carefully controlled heparin treatment. Sensitive and specific tests are the assays for fibrinogen-fibrin degradation products (FDP) and soluble complexes (SC) using the haemagglutination test or the ethanol test. The platelet count should be combined with measurement of the bleeding time. A varying degree of thrombopenia is frequent but non specific. In cases of septicemia, it is an early warning sign. A selective fall in proaccelerin is an indirect early sign. A fall in antithrombin III (AT III) is considered a good sign of DIC but it does not occur in every case, and is most liable to be present in liver failure. From the FDP and fibrinogen results, it should be clear whether one is dealing with compensated, decompensated or even over-compensated DIC. Diagnosis should be complemented by a careful search for the clinical signs of coagulation and haemorrhage. It is indispensable for investigations to be repeated every 6-12 hours, for the sake both of treatment strategy, which can be extremely difficult, and DIC monitoring.

Antithrombin III Deficiency↗

[Chemotherapy associating mitomycin C, thiotepa and vindesine in advanced breast cancers. Study of 100 cases (author's transl)].

One hundred patients suffering from advanced breast cancers and resisting to one (15) or several (85) drugs previously administered have been treated by an association of mitomycin C, thiotepa and vindesine, given every 3 weeks. Toxic effects were frequently observed and it was necessary to stop the treatment in more than 25 p. cent of the patients. Hemorrhagic complications due to thrombopenia (50 p. cent of cases) were severe in few cases and were responsible for the death of 2 patients. An overall objective response has been obtained in 41 cases and a regression in more than 50 p. cent of the lesions with a median duration of 7.5 months has been observed in 15 cases. The most striking effects have been noted in lymph nodes and skin involvement with an appreciable effect on the functional (subjective) and painful syndrome in 60 p. cent of cases. Difficulties in applying this chemotherapy to patients who had already been heavily treated explain a toxicity which would probably be reduced by an earlier application of the treatment. The quality of the results obtained (here) with these patients incite to study the effect of this association primarily to improve the long-term prognosis of localized or already disseminated breast cancers.

Adenocarcinoma↗

[Hematologic anomalies in Lyell's syndrome. Study of 26 cases].

Case records of 26 patients with Lyell Syndrome were reviewed for studying haematologic abnormalities. Eosinophilia, neutropenia, thrombopenia were uncommon. Circulating immature granulocytic cells were frequently encountered during the second week of evolution, mostly when leucocytosis was present. Anemia was frequent, the lowest haemoglobin titer beeing reached by the 15th day. Reticulocytosis was initially low and reached a peak during the second week. At that time biological markers of inflammatory syndrome were getting worse. So the originating anemia seems primarily of medullary origin and independent of inflammatory syndrome. Lymphopenia was constant and sometimes marked, with no circulating lymphocytes in two cases. The lowest numbers of lymphocytes were observed during the first week. These haematological abnormalities may have some pathogenic significance.

Anemia↗

[Systemic reactions in rats following the initiation of a local inflammatory process by subcutaneous administration of spirits of turpentine].

Local inflammation was induced in rats by single (1 x 4 ml/kg) or multiple (14 X 0.2 ml/animal) infections of turpentine. The induction of inflammatory processes in both groups resulted in anemia and granulocytosis following an initial leukopenia. Thrombopenia on the second day, followed by thrombocytosis, was also observed in both groups. Studies on blood chemistry parameters revealed a decline in serum albumin; elevation of alkaline phosphatase in serum was observed only after multiple injection of turpentine. In these animals an elevation in the weights of spleen and adrenals and a reduction in the weight of thymus were also found.

Animals↗

[Blood coagulation disorders in liver cirrhosis in relation to the degree of portal hypertension].

Investigated were the haemostasis of 45 patients with histologically confirmed liver cirrhosis. The patients were subdivided into three groups according to the extent of their porto caval collateral circulation as proved by laparoscopy, gastroscopy and radiology: I = no porto caval shunts (n = 10); II = moderate porto caval shunts (n = 13); III = distinct porto caval shunts (n = 14). A 4th group consisted of 8 patients with bleeding from oesophageal varices. The results indicated a significant decrease in the stages I-III of the coagulation factors produced in the liver (incl. factor XIII and AT III) and the thrombocytes. Unchanged remained the concentration of factor VIII, whereas the factor VIII associated antigen showed an increased activity depending on the severity of the disease (stages I-III). In patients with bleeding from oesophageal varices, values of about 300% of normal could be demonstrated. Depending on the stage of the porto caval collateral circulation, the concentration of fibrin(ogen) split products were also increased. For comparison, patients with pre- and posthepatic blockage were investigated, whose portal hypertension was not caused by liver cirrhosis. Besides a mild thrombopenia they only showed a secondary hyperfibrinolysis. The results, above all in the cases of liver cirrhosis, can be explained by pathophysiological mechanism: a decreased synthesis of clotting factors-a disturbed portal microcirculation with fibrin deposition-an impaired function of the liver RES.

Blood Coagulation Disorders↗

[Congenital deficiency of platelet alpha-granules and medullary reticulinic fibrosis. Physiopathogenic hypothesis (author's transl)].

Hematological investigations of two propositus from a family with congenital thrombopathia characterised by a moderate thrombopenia and a specific platelet alpha granule deficiency revealed that the thrombopathia was associated with a constitutive reticulinic myelofibrosis, without any sign of evolutivity. This association led us to present an hypothesis to explain the genesis of this myelofibrosis. This hypothesis is based on the potential role of a mitogenic factor(s) synthetized in megakaryocytes and transported normally by platelets in alpha granules, to induce fibroblastic proliferation and increased synthesis of collagen type III by bone marrow. This myelofibrosis is similar to that found in most of myeloproliferative disorders at some step of evolutivity. In these diseases myelofibrosis is associated with qualitative and quantitative abnormalities of platelets and megakaryocytes. These abnormalities give elements to sustain our hypothesis.

Blood Platelet Disorders↗

[Antiprothrombinase type of circulating anticoagulants during acute disseminated lupus erythematosus].

We report the observations of 4 young women suffering from SLE witha circulatig antiprothrombinase anticoagulant. Antiprothrombinase is the most frequent circulating anticoagulant found in SLE (5 to 10 p. 100). SLE is the main aetiology for antiprothrombinase (over 50 p. 100). It is called 'lupus anticoagulant'. Some symptoms seem to be more frequent in SLE with antiprothrombinase. Such are biological signs (false positive tests for syphilis. Coombs test, thrombopenia, prothrombin deficiency) and clinical signs (venous or arterial thrombosis particularly if oestroprogestative treatment is taken, bleeding if thrombocytopenia or deficiency of prothrombin; repetitive abortion and may be neuropsychiatric signs). Antiprothrombinase is an autoantibody (IgG or IgG + M) polyclonal in SLE, with antiphospholipid activity. It could decrease the production of prostacyclin (PGI2) from free arachidonic acid derived from membrane bound phospholipids. Immunological properties of antiprothrombinase could account for clinical and biological associated signs.

Acute Disease↗

[Continuous haemofiltration in encephalopathy associated with hepatic failure (author's transl)].

Thirty-one comatose patients (18 with cirrhosis of the liver, 13 with severe hepatitis) were treated with continuous haemofiltration on polyacrylonitrile membrane (AN 69). The mean duration of sessions was 45 +/- 37 h, during which 136 +/- 108 1 of ultrafiltrate were dialyzed. Sixteen patients emerged from coma, 14 (7 with cirrhosis, 7 with hepatitis) completely and 2 partially. Blood ammonium levels decreased by 47 +/- 21% during the first 24 hours. Aminoacid clearance ranged from 20 to 50 ml/min, but only non significant changes were observed in the branched-chain/aromatic aminoacid ratio. Provided the haemodynamic balance is preserved, the technique is well tolerated. The duration of dialysis depends upon the degree of thrombopenia induced. Since the long-term prognosis of both cirrhosis patients and severe hepatitis patients is unmodified, continuous haemofiltration can only be helpful in cases where hepatic regeneration is possible; failing this, liver transplantation should be considered.

Amino Acids↗