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Accumulation of 5-hydroxytryptamine by aging platelets: studies in a model of suppressed thrombopoiesis in dogs.

Thrombocytopenia was induced in healthy, male mongrel dogs by intramuscular injection of a single dose of estradiol valerate (1 mg/kg). A steady, almost linear decay of the blood platelet count starting about day 6 post-estradiol and attaining a mean value of 14 x 10(3) platelets/microliters one week later was observed. Thrombocytopenia is explained mainly by suppression of thrombocytopoiesis, as established by two independent ways: 1. Megakaryocytes in the bone marrow were markedly reduced. 2. Kinetic studies with 111In labeled autologous platelets revealed a nearly linear decay of the radioactivity and mean survival times within the expected range. The progressive reduction in the platelet count is associated with an increase in the mean age of the platelets still circulating. Following estradiol injection, platelet 5-hydroxytryptamine (5-HT) increased from a basal value of 130 +/- 30 ng/10(8) platelets (platelet count of 351 +/- 53 x 10(3) platelets/microliters) to 343 +/- 100 ng/10(8) platelets eleven days latter, when the platelet count dropped to 32 +/- 18 x 10(3) platelets/microliters. No significant changes in the number or affinity of the 5-HT uptake receptors could be demonstrated in platelets exposed in vitro and in vivo to estradiol. Our results indicate that aging platelets accumulate 5-HT, probably by a sustained exposure to the monoamine in plasma, confirming previous observations based on models in which thrombopenia was induced by immune and mechanical means.

Animals↗

[Ambulatory heparin-antivitamin K relay].

In order to reach the active threshold as quickly as possible, heparin is usually given at the onset of anticoagulant therapy. The risk of thrombopenia is reduced by early initiation of antivitamin K drugs which also simplifies the treatment regimen and reduces costs. During this transition period, the desired level of hypocoagulation is attain by two mechanisms. Treatment effectiveness, side effects and interactions must be monitored regularly with the active participation of the patient after discharge. Laboratory tests for monitoring heparin therapy, including activated cephalin time for non-fractionated heparin and anti-Xa activity for low molecular weight heparin and biweekly platelet counts are maintained. Antivitamin K therapy is initiated without a loading dose and followed with coagulation time expressed in INR (isocoagulability = 1) at regular intervals, depending on the half-life of the chosen drug, for adapting dosage. Heparin can be withdrawn when the INR has reached equilibrium between 2 and 3. For ambulatory patients, the protocol must be rigorously applied and requires at least four laboratory tests over a period of six days. Except in cases of emergency, the two treatments are given simultaneously for a period of about one week which means that the antivitamin K must be given within 72 hours in order not to override the generally accepted duration of heparin therapy of ten days.

4-Hydroxycoumarins↗

[The treatment of Paget's disease of bone with second-generation bisphosphonates via intravenous infusion].

We compared the biochemical effects and safety of pamidronate (30 mg a day for 3 consecutive days) versus clodronate (300 mg a day for 3 consecutive days) via intravenous infusion in 14 patients with Paget's disease of bone (PDB). Both drugs induced a decrease in serum alkaline phosphatase levels as well as the elimination of hydroxyproline from urine, an effect most marked in the group treated with pamidronate. The response was maintained for 6 months after the infusion in the majority of the patients. No relevant side effects were found, except post-infusion febricula and in one patient, self-limiting thrombopenia 6 months after the infusion. We conclude that the intravenous infusion of either of the two drugs may constitute a safe and effective alternative for treatment of PDB with marked biochemical activity or resistant to conventional therapy.

Aged↗

[Adjuvant corticoid administration within the scope of HIV disease. Indications in wasting syndrome and other diseases within the scope of AIDS].

While at the start of the AIDS epidemic, corticosteroids were considered to be contraindicated, about 10 indications have since been identified for the specific use of glucocorticoids in HIV infection. Some of these indications have already been confirmed in controlled scientific studies, for example, pneumocystis carinii pneumonia or HIV-induced high-grade non-Hodgkin's lymphoma. In the case of other indications, for example, cerebral toxoplasmosis or certain forms of the wasting syndrome, clinical observational studies and, in particular, empirical data provided by large groups working on AIDS, are available. The use of corticoids for such other indications as pulmonary involvement in the case of Kaposi's sarcoma, or thrombopenia in HIV patients, is still experimental. To date, the initially feared high rate of side effects due to the theoretically possible impairment of immunological function, has not been observed. The effect of the corticosteroids appears to be concentrated more in their anti-inflammatory action than in substitution in the event of adrenal insufficiency. The carefully considered and selective use of corticosteroids can both improve the quality of life and lengthen the life expectancy of many HIV victims.

AIDS-Related Opportunistic Infections↗

[Blue phlebitis with exo- and endo-caval filters: 5 case reports].

5 cases of phlegmatia caerula dolens have been observed after the fixation of a cava blocking. You will find below the characteristics of the case reports: Mean age of patients: 69.2, from 55 to 83. Early phlegmatiae caeruleae dolens: 2 cases; late phlegmatiae: 3 cases (3 and 4 years after the cava ligature). Clinical context: advanced age; general state alteration 1 case; artery predisposition: 2 cases; heparin thrombopenia: 1 case. Responsible material: ombrelle de Mobin Uddin: 3 cases; Adams-De Weese's Clip: 2 cases. Current filters are probably less thrombogenous. Nevertheless, these case reports make us aware of the fact that in case of predisposition and/or in case of precary hemodynamic conditions, any factor likely to generate or worsen a venous stasis can originate (immediately or later) a significant thrombosis and, particularly in a few conditions, a phlegmatia caerulea dolens. Consequently, partial cava blocking indications must be seriously taken into consideration and saved for cases in which embolic risk is patent.

Age Factors↗

Acute side effects of homologous interleukin-3 in rhesus monkeys.

Interleukin-3 treatment of juvenile rhesus monkeys elicits a dose- and time-dependent syndrome that includes urticaria, palpable lymph nodes, splenomegaly, thrombocytopenia, anemia, vomiting, diarrhea, intestinal bleeding, edema, and arthritis, apart from a strong stimulation of hemopoiesis. Arthritis was found to occur significantly more often in animals expressing the major histocompatibility complex alleles B9 and Dr5. Histological analysis revealed an abundance of mast cells in urticaria and, to a lesser extent, in lungs and synovia of arthritic joints. Active osteoclasts were abundant in ribs and arthritic joints. Extramedullary hemopoiesis was encountered in liver, spleen, and kidneys. The spleen showed deposits of hemosiderin, and in the liver, Kupffer cells were loaded with iron, indicating enhanced turnover of hemoglobin. Lymph nodes and bone marrow showed macrophages involved in hemophagocytosis, which probably contributed to the development of anemia and thrombopenia. Biochemical parameters in sera were indicative of parenchymal liver damage, with cholestasis and increased erythrocyte destruction. The side effects were strongly reduced in monkeys subjected to total body irradiation just before interleukin-3 treatment. Histamine antagonists were not significantly effective in preventing side effects, which is explained by the perpetual stimulation of basophilic granulocytes by exogenous interleukin-3. The nature of the side effects indicates that interleukin-3 may be involved in the pathogenesis of acute type hypersensitivity reactions and arthritis.

Anemia↗

[Therapeutic management of antiphospholipid antibody syndrome in pregnancy].

The antiphospholipid syndrome, recently described, associates thromboembolism risks, fetal losses and thrombopenia. An obstetrical survey of this syndrome implies previous analyses of maternal and fetal risks and leads to treatment which may associate low doses of aspirin, heparin, corticoids. This complex syndrome offers the best example of materno-fetal medicine usefulness.

Adrenal Cortex Hormones↗

Ambulatory chronotherapy with 5-fluorouracil, folinic acid, and carboplatin for advanced non-small cell lung cancer. A phase II feasibility trial.

Thirty-two patients with advanced non-small cell lung carcinoma (NSCLC) received a chronomodulated 5-day venous infusion of 5-fluorouracil (5 FU) (700 mg/m2/day), folinic acid (F) (300 mg/m2/day), and carboplatin (C) (40, 50, or 55 mg/m2/day), as first chemotherapy. Courses were repeated every 21 days (after a 16-day interval). In total, 158 courses (median: 4, range: 1 through 16; 81 and 58 courses at, respectively, a 40 and 50 to 55 mg/m2 daily dosage of C) were delivered using a multichannel programmable in-time pump (Intelliject, Aguettant) connected to a double lumen implanted venous side-port. The administration was allowed in fully ambulatory convenience. Overall tolerance was excellent. Grade 3 of 4 hematologic toxicity was encountered in 4.6% of courses for thrombopenia and in 7.0% of courses for neutropenia. Nausea or vomiting (grade 3 or 4) occurred in 7.8% of courses. Mucositis, diarrhea, alopecia, or skin grade 3 or 4 toxicity were observed in less than 3% of courses. Treatment delay was needed in only 7.8% of courses and dose reductions were needed in 4.6% of courses for 5 FU and in 6.5% of courses for C. This good tolerance allowed a sustained quality of life and prompted further trials aiming to define the place of this protocol in the multidisciplinary treatment approach of NSCLC.

Adult↗

[Predictive analysis of the response to treatment with diuretics of patients with liver cirrhosis and ascites].

Our aim was to develop and validate a prognostic model to predict the evolution of cirrhotic patients admitted to the hospital because of ascites and treated with diuretics. Two hundred and two patients were evaluated. After collection of clinical and laboratory data, a prognosis of the response to diuretics was given by one of us. After univariate analysis, 37 parameters were used to construct a database. A new prognosis was obtained for each patient comparing his/her data with the database, with the help of a computer and using Bayes' theorem. Gender: female, poor general status, disturbed consciousness, increased serum glucose, increased BUN, low prothrombin time, increased bilirubin, leucocytosis, thrombopenia and low urine sodium were associated with a poor response to diuretics. Sensitivity and specificity of clinical and computer prognosis were similar. Computer prognosis allowed the classification of patients in groups of risk which showed a different evolution and improved the accuracy of the clinical prognosis. We conclude that the objective analysis of clinical and laboratory data is useful to improve the accuracy of the prediction of the evolution in cirrhotic patients with ascites treated with diuretics.

Ascites↗

[Liver transplantation as school for visceral surgery--experiences for perioperative management].

Liver transplantation is one of the most extensive operations in visceral surgery. Preexisting cardiopulmonary abnormalities, disturbances of glucose, hormone, and electrolyte metabolism and cirrhosis-associated diseases, including hypersplenism with thrombopenia and severe coagulopathy, require advanced surgical skills. Optimal perioperative intensive care management is necessary because of the patient's immunosuppressed condition. In principle, patient management after liver transplantation is similar to that performed after major visceral surgery. However, special attention should be paid to initial liver perfusion and function. Like for sepsis in visceral surgery, in liver transplantation monitoring of cytokines and other mediators is important. New approaches for bioartificial liver support in patients with acute liver failure have primarily been developed as a bridging system to liver transplantation, but they may also be of value for patients with septic liver failure or liver failure after major liver resections.

Artificial Organs↗

[Ganciclovir prophylaxis for cytomegalovirus interstitial pneumonitis after allogeneic bone marrow transplantation].

We evaluated the efficacy of ganciclovir to prevent the development of cytomegalovirus interstitial pneumonitis (CMV-IP) in patients with bone marrow transplants. Of 35 patients enrolled in this study, 33 were seropositive for CMV or had seropositive donors, and two were seronegative before transplant but were positive for CMV examined by polymerase chain reaction (PCR) on days 30-37. Ganciclovir was given at a dose of 250 mg/body daily from day 30-37 to day 70. Blood, throat swabs, urine and bronchoalveolar-lavage fluid (BALF) were screened for CMV by PCR on days 30-37, 70 and 100. CVM-IP developed in two of 35 patients (5.7%) who received ganciclovir for prophylaxis, as compared with six of 39 historical controls who did not receive ganciclovir. A significant reduction of CMV detection by PCR in blood, throat swabs, and BALF was observed after administration of ganciclovir, on day 70. The incidence of neutropenia, thrombopenia and renal impairment in the study period showed no difference between the study group and the historical control. Early prophylactic use of ganciclovir appears to reduce the risk of CMV disease in allogeneic transplant recipients with positive serology or positive CMV-PCR.

Adolescent↗

[VP 16-213 in combination with endoxan, methotrexate and oncovin as polychemotherapy for bronchogenic carcinoma].

Thirty patients with bronchogenic carcinoma underwent an 8 week course of induction therapy consisting of cyclophosphamide, methotrexate, vincristine, and VP 16-213 (NSC 141 540). Those who achieved objective remission or tumor stabilization were then placed on an intermittent treatment schedule with the same drugs. Of the 30 patients, 17 had an objective response, 5 were unchanged and 8 progressed. Responses were more frequent in anaplastic carcinoma (13/19) than epidermoid or adenocarcinoma (4/11). The toxicity mainly consisted of leukopenia, thrombopenia, alopecia, nausea and vomiting. The implications of these findings in the planning of further chemotherapeutic programs are discussed.

Adenocarcinoma↗

[Carboplatin and cyclophosphamide in stage Ic-IV ovarian carcinoma: retrospective study of 101 cases].

We report our experience of CBDCA-CPM combination chemotherapy as first line therapy in 101 ovarian cancers. The therapeutic scheme was: initial cytoreductive surgery followed by six chemotherapy cycles (CBDCA 400 mg/m2/d IV dl, CPM 600 mg/m2/d IV dl, dl = d21) and second-look laparotomy. The initial stages were four Ic, three IIa, four IIb, four IIc, 15 IIIa, 28 IIIb, 23 IIIc and 20 IV. After initial surgery, there were 39 macroscopic residual diseases superior to 2 cm, 26 macroscopic residual diseases inferior or equal to 2 cm, four microscopic diseases and no residual disease in 30 cases (unknown in two cases). The overall response rate to chemotherapy was 83% with 56% histologic complete response rate. The main toxicity was haematological with 60% of leucopenia grade III-IV, 52% of thrombopenia grade III-IV. Age at diagnosis, residual disease after first look surgery and length of CA 125 normalization were significant prognostic factors for survival in this series.

Adolescent↗

Phase I/II study of paclitaxel, cisplatin, and cyclophosphamide in advanced ovarian carcinoma: preliminary results.

In this phase I/II study, we assessed the impact of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of advanced ovarian carcinoma combined with the standard regimen cisplatin/cyclophosphamide given as follows: paclitaxel 175 mg/m2 (over 3 hours perfusion with standard premedication), cisplatin 80 mg/m2 (6 to 12 hours after paclitaxel), and cyclophosphamide 400 mg/m2. From February 1994 to January 1996, 27 patients (median age, 55 years; age range, 35 to 74 years) were entered into the study. Eight patients had distant metastases and 19 had early locoregional disease (stage III, 18 patients; stage IC, one patient). Twenty-two patients had undergone prior surgery (simple biopsy, six patients; optimally debulked, nine patients; suboptimally debulked, seven patients). Twenty-one patients had received no prior chemotherapy and six were previously treated with at least one platinum-based regimen. A maximum of six courses of paclitaxel/cisplatin/cyclophosphamide were given every 21 days. Twenty-three patients were evaluable for toxicity: neutropenia (World Health Organization grade 3/4), 91% of patients; thrombopenia (World Health Organization grade 3/4), 13% of patients; two episodes of neutropenia with fever; and neurotoxicity grade 3, 17% of patients. Alopecia grade 3 was reported in all patients. No hypersensitivity reactions and no cardiac toxicity was observed. Among 17 patients evaluable for response (patients with stage IV disease or stage III suboptimally debulked), 12 (70%) clinical complete responses (CRs) and three (18%) partial responses were observed. Among the 12 patients with CRs, 10 underwent second-look laparotomy and seven of them (70%) achieved a pathologic CR. In the group of 11 chemotherapy-naive patients evaluable for response, eight (72%) achieved a CR and three (28%) achieved a partial response. This combination seems to be safe, with very acceptable toxicity, and also seems to be highly active in the treatment of patients with advanced ovarian carcinoma.

Adult↗

[Forensic medical implications of anticoagulant treatments].

Several types of accidents related to anticoagulant treatment can lead to legal procedures, including: thromboembolic post-operative complications associated with lack of anticoagulant prophylaxis and leading to sequelae or death; severe hemorrhagic or thromboembolic accidents attributed to poor management of anticoagulant therapy; complications with sequelae or death resulting from heparin-induced thrombopenia, either with standard or low-molecular weight heparin and associated with poor surveillance of platelet counts. The exceptional nature of accidents leading to legal procedures (24 legal cases in Pr Natali's experience) and the small number of other cases reported should not lead to underestimating the importance of precise rules for anticoagulation treatments. In 7 cases, there was no anticoagulant prophylaxis after surgery. Recent consensus conferences have proposed a definition of small, moderate or high risk of thrombosis as a function of patient status and surgical procedure. Expert working groups have defined the operated patients for which pharmacological anti-coagulation is necessary. In 19 other cases, management of the treatment protocol was insufficient leading to severe hemorrhage with sequelae, severe thromboembolism, or late diagnosis of heparin-induced thrombocytopenia because of insufficient surveillance of platelet counts. Recent advances in laboratory tests for the diagnosis of heparin-induced thrombocytopenia should be emphasized. To these case reports can be added other observations in a small number of complaints resulting from unadvisable treatment combinations, poor surveillance of a thromboembolic event or dangerous invasive exploration.

Adult↗

Polyclonal B-cell lymphocytosis with features resembling hairy cell leukemia-Japanese variant.

Polyclonal B lymphocytosis was found in four patients having clinical and hematologic features resembling those of hairy cell leukemia (HCL). All four patients were women between 37 and 67 years of age. Three patients had splenomegaly. Lymphadenopthy was absent or slight. Persistent lymphocytosis was seen in all the patients, and anemia and/or thrombopenia was observed in three of the patients. Abnormal lymphocytes have long microvilli and prominent membranous ruffles on their surfaces. Bone marrow aspirates and biopsy specimens showed increased numbers of abnormal lymphocytes with round nuclei and abundant pale cytoplasm. Although these findings were similar to those of HCL, studies of Ig gene rearrangements and expression showed the polyclonal proliferation of B cells. We called this new disease hairy B-cell lymphoproliferative disorder (HBLD). All four patients exhibited a polyclonal increase in serum IgG. The morphology of the cells in HBLD was more similar to that of leukemia cells of a variant form of HCL (HCL-Japanese variant) than to typical HCL cells. The surface IgG+, CD5-, CD11c+, CD22+, CD24-, CD25- phenotype and the weak tartrate-resistant acid phosphatase activity in the cells were identical to those of HCL cells of the Japanese variant. Our findings suggest that the B cells in HBLD are the nonmalignant counterpart of leukemic B cells in HCL-Japanese variant.

Adult↗

[HELLP syndrome. Review and update].

Whether HELLP syndrome is a distinct entity or a severe form of preeclampsia, it remains a factor of gravity. Described by Weinstein in 1982, it associates hemolysis, cytolysis (elevated liver enzymes) and thrombopenia (low platelets). The cut off for the biological parameters have to be strictly defined to avoid overdiagnosis of HELLP syndrome. The difficulty to diagnose this syndrome is real because most of the associated clinical signs are aspecific. The errors of diagnosis are more frequent when the syndrome is not associated to preeclampsia (10%), in the mid-trimester (15%) and in the postpartum (30%). The mean term of delivery is 32 weeks, the prematurity being widely induced because of the fear of maternal complications. Maternal deaths (1.1%) do not seem to be directly related to the HELLP syndrome. Subcapsular hematomas of the liver are unfrequent (0.9%). Rapid termination of pregnancy, by vaginal delivery or by cesarean, is generally recommended when the fetal lung maturity is obtained or when maternal complications appear. Conversely, conservative management is acceptable before 32 weeks. Corticosteroid therapy or hemodynamic therapy could allow to obtain fetal lung maturity. A conservative approach requires permanent materno-fetal follow-up which can only be achieved in a perinatal center integrating a neonatal intensive care unit.

Adrenal Cortex Hormones↗

[Thrombocytopenic purpura after isolated or combined vaccination against measles, mumps and rubella].

A retrospective epidemiological survey was conducted to evaluate the incidence and characteristics of thrombocytopenic purpura (TP) reported in France following measles, mumps or rubella vaccination with monovalent or multivalent vaccines. Sixty cases of TP were reported i.e an incidence/100,000 doses of 0.23 and 0.17 for measles or rubella vaccines respectively given alone, to 0.87 for combined measles-rubella vaccine and 0.95 for MMR vaccine. The mean age was 21 +/- 12 months and the delay of diagnosis was 16 +/- 6 days after vaccination. Thrombopenia was severe (mean platelet count: 8000 +/- 6000/mm3) and always associated with purpura. The immediate outcome was favourable in 89.5 per cent of cases. Vaccine-associated TP appears to be similar to acute childhood idiopathic thrombocytopenic purpura but the clear temporal relationship between MMR vaccination and the occurrence of TP make a causal relationship highly plausible. Acute TP seems a rare complication of measles-rubella and MMR vaccination but clinicians had to be informed of the possibility of their occurrence. Acute TP following vaccination should be reported by physicians to their Regional Drug Surveillance Centre.

Child↗