Tranexamic Acid for Hyperfibrinolytic Hemorrhage During Conservative Management of Placenta Percreta

BACKGROUND:Complications of conservative management of abnormal placentation in which the placenta is left in situ for resorption include secondary hemorrhage, infection, and disseminated intravascular coagulation.CASE:A 41-year old woman received conservative treatment for placenta percreta. Nine weeks after delivery, she developed gingival bleeding, easy bruising, and moderate-to-severe vaginal bleeding. Hemostasis testing established the diagnosis of isolated hyperfibrinolysis; acute disseminated intravascular coagulation was excluded. Bleeding was successfully treated using the antifibrinolytic agent tranexamic acid. Eight weeks later uncomplicated curettage was performed.CONCLUSION:Isolated hyperfibrinolysis is a potential cause of bleeding during conservative management of placenta increta and percreta. Management of this treatment approach should include hemostasis monitoring, because hyperfibrinolysis can be successfully controlled using fibrinolysis inhibitors

Massive hypercoagulable state despite full-dose anticoagulant treatment in a patient with occult malignancy: considerations concerning chemotherapy without definitive diagnosis

A 55-year-old female patient presented with recurrent deep venous thrombosis and pulmonary embolism while on oral anticoagulant treatment using the vitamin K antagonist phenprocoumon. Hypercoagulable state was regarded to be paraneoplastic, but no underlying malignancy could be identified despite extensive screening for cancer, including gastroscopy and colonoscopy, a bone marrow biopsy, thoracoabdominal CT scans with subsequent biopsies of possibly malignant findings, octreotide scintigraphy, skeletal scintigraphy and gynaecological screening. In the course of her hospital stay she developed progressive right cardiac insufficiency due to the formation of new thromboses despite aggressive anticoagulant treatment and died of right-sided heart failure. The autopsy showed a poorly differentiated adenocarcinoma in the middle lobe of the right lung. In addition, pulmonary lymphangiosis carcinomatosa, pleural and pericardial carcinosis, and lymph node metastases and osteoblastic vertebral body metastases were shown

Impact of Hormone-Associated Resistance to Activated Protein C on the Thrombotic Potential of Oral Contraceptives: A Prospective Observational Study

Introduction: The increased thrombotic risk of oral contraceptives (OC) has been attributed to various alterations of the hemostatic system, including acquired resistance to activated protein C (APC). To evaluate to what extent OC-associated APC resistance induces a prothrombotic state we monitored plasma levels of thrombin and molecular markers specific for thrombin formation in women starting OC use. Elevated plasma levels of thrombin have been reported to characterize situations of high thrombotic risk such as trauma-induced hypercoagulability, but have not yet been studied during OC use. Patients and Methods: Blood samples were collected prospectively from healthy women (n = 21) before and during three menstruation cycles after start of OC. APC resistance was evaluated using a thrombin generation-based assay. Plasma levels of thrombin and APC were directly measured using highly sensitive oligonucleotide-based enzyme capture assay (OECA) technology. Thrombin generation markers and other hemostasis parameters were measured additionally. Results: All women developed APC resistance as indicated by an increased APC sensitivity ratio compared with baseline after start of OC (p = 0.0003). Simultaneously, plasma levels of thrombin, prothrombin fragment 1+2, and of thrombin-antithrombin complexes did not change, ruling out increased thrombin formation. APC plasma levels were also not influenced by OC use, giving further evidence that increased thrombin formation did not occur. Conclusions: In the majority of OC users no enhanced thrombin formation occurs despite the development of APC resistance. It cannot be ruled out, however, that thrombin formation might occur to a greater extent in the presence of additional risk factors. If this were the case, endogenous thrombin levels might be a potential biomarker candidate to identify women at high thrombotic risk during OC treatment. Large-scale studies are required to assess the value of plasma levels of thrombin as predictors of OC-associated thrombotic risk

Tamoxifen induces resistance to activated protein C

Introduction: The estrogen antagonist tamoxifen (TAM) increases the thrombotic risk similar to estrogen containing oral contraceptives (OC). In OC users this risk is attributed to alterations of hemostasis resulting in acquired resistance to activated protein C (APC). TAM-induced APC resistance has not been reported yet. Materials and Methods: Blood samples were collected prospectively from women with breast cancer before (n= 25) and monthly after start of adjuvant TAM treatment (n = 75). APC resistance was evaluated on basis of the effect of APC on the endogenous thrombin generation potential. To detect increased in vivo APC generation APC plasma levels were measured using a highly sensitive oligonucleotide-based enzyme capture assay. Routine hemostasis parameters were measured additionally. Results: APC sensitivity decreased by 41% (p= 0.001) compared to baseline after one month of TAM application and remained significantly decreased during the study period. Free protein S increased (p= 0.008) while other analyzed procoagulant factors, inhibitors, and activation markers of coagulation decreased or did not change significantly. In five patients the APC concentration increased to non-physiological levels but an overall significant increase of APC was not observed. Conclusions: This is the first study showing acquired APC resistance under TAM therapy. Acquired APC resistance might explain the increased thrombotic risk during TAM treatment. Observed changes of hemostasis parameters suggest different determinants of TAM-induced APC resistance than in OC-induced APC resistance. The presence of acquired APC resistance in TAM patients warrants further evaluation if these patients may benefit from antithrombotic prophylaxis in the presence of additional thrombotic risk factors. (C) 2014 Elsevier Ltd. All rights reserved

M.: Multimedia instruction in safe and secure systems

Abstract. The aim of the MMiSS project is the construction of a multimedia Internet-based adaptive educational system. Its content will initially cover a curriculum in the area of Safe and Secure Systems. Traditional teaching materials (slides, handouts, annotated course material, assignments, and so on) are to be converted into a new hypermedia format, integrated with tool interactions for formally developing correct software; they will be suitable for learning on campus and distance learning, as well as interactive, supervised, or co-operative self-study. To ensure “sustainable development”, i.e. continuous long-term usability of the contents, coherence and consistency are especially emphasised, through extensive semantic linking of teaching elements and a particular version and configuration management, based on experience in formal software development and associated support tools.

IRF6 gene variants in Central European patients with non-syndromic cleft lip with or without cleft palate

Variants in the interferon regulatory factor 6 (IRF6) gene have repeatedly been associated with non-syndromic cleft lip with or without cleft palate (NSCL/P). A recent study has suggested that the functionally relevant variant rs642961 is the underlying cause of the observed associations. We genotyped rs642961 in our Central European case-control sample of 460 NSCL/P patients and 952 controls. In order to investigate whether other IRF6 variants contribute independently to the etiology of NSCL/P, we also genotyped the non-synonymous coding variant V274I (rs2235371) and five IRF6-haplotype tagging single nucleotide polymorphisms (SNPs). A highly significant result was observed for rs642961 (P = 1.44 x 10-6) in our sample. The odds ratio was 1.75 [95% confidence interval (CI): 1.38-2.22] for the heterozygous genotype and 1.94 (95% CI: 1.21-3.10) for the homozygous genotype, values that are similar to those reported in a previously published family-based study. Our results thus confirm the involvement of the IRF6 variant, rs642961, in the etiology of NSCL/P in the Central European population. We also found evidence suggestive of an independent protective effect of the coding variant V274I. In order to understand fully the genetic architecture of the IRF6 locus, it will be necessary to conduct additional SNP-based and resequencing studies using large samples of patients

MultiMedia Instruction in

The aim of the MMiSS project is the construction of a multimedia Internet-based adaptive educational system. Its content will initially cover a curriculum in the area of Safe and Secure Systems. Traditional teaching materials (slides, handouts, annotated course material, assignments, and so on) are to be converted into a new hypermedia format, integrated with tool interactions for formally developing correct software; they will be suitable for learning on campus and distance learning, as well as interactive, supervised, or co-operative self-study

Nonsyndromic Cleft Lip with or without Cleft Palate: Increased Burden of Rare Variants within Gremlin-1, a Component of the Bone Morphogenetic Protein 4 Pathway

Background: The genes Gremlin-1 (GREM1) and Noggin (NOG) are components of the bone morphogenetic protein 4 pathway, which has been implicated in craniofacial development. Both genes map to recently identified susceptibility loci (chromosomal region 15q13, 17q22) for nonsyndromic cleft lip with or without cleft palate (nsCL/P). The aim of the present study was to determine whether rare variants in either gene are implicated in nsCL/P etiology. Methods: The complete coding regions, untranslated regions, and splice sites of GREM1 and NOG were sequenced in 96 nsCL/P patients and 96 controls of Central European ethnicity. Three burden and four nonburden tests were performed. Statistically significant results were followed up in a second case-control sample (n=96, respectively). For rare variants observed in cases, segregation analyses were performed. Results: In NOG, four rare sequence variants (minor allele frequency <1%) were identified. Here, burden and nonburden analyses generated nonsignificant results. In GREM1, 33 variants were identified, 15 of which were rare. Of these, five were novel. Significant p-values were generated in three nonburden analyses. Segregation analyses revealed incomplete penetrance for all variants investigated. Conclusion: Our study did not provide support for NOG being the causal gene at 17q22. However, the observation of a significant excess of rare variants in GREM1 supports the hypothesis that this is the causal gene at chr. 15q13. Because no single causal variant was identified, future sequencing analyses of GREM1 should involve larger samples and the investigation of regulatory elements. (C) 2014 Wiley Periodicals, Inc