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- Systematic Analysis of Bleeding Phenotype in PT-VWD Compared to Type 2B VWD Using an Electronic Bleeding Questionnaire. [JOURNAL ARTICLE]
- Clin Appl Thromb Hemost 2014 Jul 25.
To investigate the utility of an electronic version of the condensed molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (VWD) bleeding questionnaire (eBQ) in assessing the bleeding phenotype in platelet-type VWD (PT-VWD) and compare it to its closely similar disorder, type 2B VWD.Retrospective analysis of the clinical bleeding and laboratory phenotype of 13 patients with PT-VWD and 12 type 2B VWD.Bleeding score (BS) was significantly lower in PT-VWD as compared to type 2B. Bleeding score correlated with platelet count and von Willebrand factor:Ristocetin cofactor activity in PT-VWD but not in type 2B with a significant reduction in platelet count in type 2B VWD compared to PT-VWD. The eBQ had sensitivity of 62% in PT-VWD and 92% in type 2B VWD.Objective analysis of bleeding symptoms further the understanding of the phenotype of 2 closely similar bleeding disorders for better diagnosis and follow-up. Larger international prospective studies are warranted to evaluate the utility of the eBQ in PT-VWD and other rare bleeding disorders.
- Successful treatment of severe thrombocytopenia with the use of thrombopoeitin receptor agonist eltrombopag in a patient with chronic myelomonocytic leukemia. [JOURNAL ARTICLE]
- J Oncol Pharm Pract 2014 Jul 24.
Chronic myelomonocytic leukemia (CMML) is a clonal disorder of hematopoietic stem cells often occurring in elderly patients. The combination of CMML with autoimmune manifestations, including immune-mediated thrombocytopenia, has been described before in a number of case reports. To our knowledge, this is the first reported case of the successful treatment of CMML-related thrombocytopenia with a thrombopoeitin receptor agonist, eltrombopag.
- Treatment of resistant metastatic melanoma using sequential epigenetic therapy (decitabine and panobinostat) combined with chemotherapy (temozolomide). [JOURNAL ARTICLE]
- Cancer Chemother Pharmacol 2014 Jul 26.
To explore the safety and tolerability of combining two epigenetic drugs: decitabine (a DNA methyltransferase inhibitor) and panobinostat (a histone deacetylase inhibitor), with chemotherapy with temozolomide (an alkylating agent). The purpose of such combination is to evaluate the use of epigenetic priming to overcome resistance of melanoma to chemotherapy.A Phase I clinical trial enrolling patients aged 18 years or older, with recurrent or unresectable stage III or IV melanoma of any site. This trial was conducted with full Institutional Review Board approval and was registered with the National Institutes of Health under the clinicaltrials.gov identifier NCT00925132. Patients were treated with subcutaneous decitabine 0.1 or 0.2 mg/kg three times weekly for 2 weeks (starting on day 1), in combination with oral panobinostat 10, 20, or 30 mg every 96 h (starting on day 8), and oral temozolomide 150 mg/m(2)/day on days 9 through 13. In cycle 2, temozolomide was increased to 200 mg/m(2)/day if neutropenia or thrombocytopenia had not occurred. Each cycle lasted 6 weeks, and patients could receive up to six cycles. Patients who did not demonstrate disease progression were eligible to enter a maintenance protocol with combination of weekly panobinostat and thrice-weekly decitabine until tumor progression, unacceptable toxicity, or withdrawal of consent.Twenty patients were initially enrolled, with 17 receiving treatment. The median age was 56 years. Eleven (65 %) were male, and 6 (35 %) were female. Eleven (64.7 %) had cutaneous melanoma, 4 (23.5 %) had ocular melanoma, and 2 (11.8 %) had mucosal melanoma. All patients received at least one treatment cycle and were evaluable for toxicity. Patients received a median of two 6-week treatment cycles (range 1-6). None of the patients experienced DLT. MTD was not reached. Adverse events attributed to treatment included grade 3 lymphopenia (24 %), anemia (12 %), neutropenia (12 %), and fatigue (12 %), as well as grade 2 leukopenia (30 %), neutropenia (23 %), nausea (23 %), and lymphopenia (18 %). The most common reason for study discontinuation was disease progression.This triple agent of dual epigenetic therapy in combination with traditional chemotherapy was generally well tolerated by the cohort and appeared safe to be continued in a Phase II trial. No DLTs were observed, and MTD was not reached.
- Paclitaxel, ifosfamide, and cisplatin (TIP) as salvage and consolidation chemotherapy for advanced germ cell tumor. [JOURNAL ARTICLE]
- J Cancer Res Clin Oncol 2014 Jul 26.
The purpose of the study was to assess the efficacy of TIP as salvage chemotherapy for germ cell tumor (GCT) patients with relapsed disease or cisplatin (CDDP)-refractory disease and consolidation chemotherapy for patients who responded unfavorably to first-line chemotherapy.Forty-three patients with advanced GCT were treated with TIP. Eleven with relapsed disease and five with CDDP-refractory disease received TIP as salvage chemotherapy. The remaining 27 received TIP as consolidation chemotherapy following initial induction chemotherapy. All patients received prophylactic granulocyte colony-stimulating factor.In total, 116 cycles of TIP were administered with a median of three cycles (range 1-4 cycles) per patient. Before TIP, 33 patients showed elevated tumor marker and 23 patients (70 %) achieved marker normalization with the chemotherapy. One of six (17 %) patients with refractory disease and 5 of 10 (50 %) patients with relapsed disease achieved durable complete response (CR) after TIP with or without surgery. Eighteen of 27 (67 %) patients receiving TIP as consolidation chemotherapy achieved durable CR. Five additional patients were given further chemotherapy and achieved durable CR. Grade 4 leukocytopenia and thrombocytopenia were observed in 91 and 42 % of patients, respectively; all were managed with routine supportive care. Grade 2 and grade 3 sensory neuropathy was observed in 37 and 2 % of patients, respectively.The TIP was effective for relapsed patients with favorable risk features and selected CDDP-refractory GCT patients. Results of TIP as consolidation for patients with unfavorable response to the initial chemotherapy were also encouraging. The toxicities were mainly myelosuppression and sensory neuropathy.
- Proteasome function is required for platelet production. [JOURNAL ARTICLE]
- J Clin Invest 2014 Jul 25.
The proteasome inhibiter bortezomib has been successfully used to treat patients with relapsed multiple myeloma; however, many of these patients become thrombocytopenic, and it is not clear how the proteasome influences platelet production. Here we determined that pharmacologic inhibition of proteasome activity blocks proplatelet formation in human and mouse megakaryocytes. We also found that megakaryocytes isolated from mice deficient for PSMC1, an essential subunit of the 26S proteasome, fail to produce proplatelets. Consistent with decreased proplatelet formation, mice lacking PSMC1 in platelets (Psmc1fl/fl Pf4-Cre mice) exhibited severe thrombocytopenia and died shortly after birth. The failure to produce proplatelets in proteasome-inhibited megakaryocytes was due to upregulation and hyperactivation of the small GTPase, RhoA, rather than NF-κB, as has been previously suggested. Inhibition of RhoA or its downstream target, Rho-associated protein kinase (ROCK), restored megakaryocyte proplatelet formation in the setting of proteasome inhibition in vitro. Similarly, fasudil, a ROCK inhibitor used clinically to treat cerebral vasospasm, restored platelet counts in adult mice that were made thrombocytopenic by tamoxifen-induced suppression of proteasome activity in megakaryocytes and platelets (Psmc1fl/fl Pdgf-Cre-ER mice). These results indicate that proteasome function is critical for thrombopoiesis, and suggest inhibition of RhoA signaling as a potential strategy to treat thrombocytopenia in bortezomib-treated multiple myeloma patients.
- Severe Fever with Thrombocytopenia Syndrome Virus in Ticks Collected from Humans, South Korea, 2013. [JOURNAL ARTICLE]
- Emerg Infect Dis 2014 Aug; 20(8):1358-1361.
We investigated the infection rate for severe fever with thrombocytopenia syndrome virus (SFTSV) among ticks collected from humans during May-October 2013 in South Korea. Haemaphysalis longicornis ticks have been considered the SFTSV vector. However, we detected the virus in H. longicornis, Amblyomma testudinarium, and Ixodes nipponensis ticks, indicating additional potential SFTSV vectors.
- Antibodies against Severe Fever with Thrombocytopenia Syndrome Virus in Healthy Persons, China, 2013. [JOURNAL ARTICLE]
- Emerg Infect Dis 2014 Aug; 20(8):1355-1357.
In June 2013, a subclinical infection with severe fever with thrombocytopenia syndrome virus (SFTSV) was detected in Zhejiang Province, China, prompting seroprevalence studies in 6 districts within the province. Of 986 healthy persons tested, 71 had IgG antibodies against SFTSV. This finding suggests that most natural infections with SFTSV are mild or subclinical.
- A new form of macrothrombocytopenia induced by a germline mutation in PRKACG gene. [JOURNAL ARTICLE]
- Blood 2014 Jul 24.
Macrothrombocytopenias are the most important subgroup of inherited thrombocytopenias. This subgroup is particularly heterogeneous because the affected genes are involved, in so various functions as cell signaling, cytoskeleton organization and gene expression. Herein we describe the clinical and hematological features of a consanguineous family with a severe autosomal recessive macrothrombocytopenia associated with a thrombocytopathy inducing a bleeding tendency in the homozygous mutated patients. Platelet activation and cytoskeleton reorganization were impaired in these homozygous patients. Exome sequencing identified a c.222C>G mutation (missense p.74Ile>Met) in PRKACG, a gene encoding the γ-catalytic subunit of the cAMP-dependent protein kinase, the mutated allele cosegregating with the macrothrombocytopenia. We demonstrate that the p.74Ile>Met PRKACG mutation is associated with a marked defect in proplatelet formation and a low level in filamin A in megakaryocytes (MKs). The defect in proplatelet formation was rescued in vitro by lentiviral vector-mediated over-expression of wild-type PRKACG in patient MKs. We thus conclude that PRKACG is a new central actor in platelet biogenesis, and a new gene involved in inherited thrombocytopenia with giant platelets associated with a thrombocytopathy.
- Prediction of IVIG treatment efficiency in fetal/neonatal alloimmune thrombocytopenia. [Letter]
- Blood 2014 Jul 24; 124(4):654-5.
- Acquired Bleeding Disorders. [REVIEW]
- Emerg Med Clin North Am 2014 Aug; 32(3):691-713.
Emergency medicine practitioners treat bleeding patients on a regular basis. Disorders of hemostasis are an additional challenge in these patients but can be assessed and managed in a systematic fashion. Of particular importance to the emergency clinician are the iatrogenic causes of abnormal hemostasis. Other acquired causes of abnormal hemostasis include renal disease, immune thrombocytopenia, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, acquired coagulation factor inhibitors, acute traumatic coagulopathy, liver disease, and disseminated intravascular coagulopathy.