Search

Venous thromboembolic disease (VTE) risk increases five-fold antenatally and 14-fold during the puerperium. Obesity significantly increases this risk. The D-dimer assay and more novel Calibrated Automated Thrombogram (CAT) assay laboratory tests display potential for use in VTE risk stratification in pregnancy, although to date, research in the performance characteristics of these tests in obese and nonobese pregnant populations is limited. The aim of this study was to compare D-dimer and thrombin generation levels in obese and nonobese pregnant women. Pregnant women were recruited and categorised, as obese (BMI ≥30) or nonobese (BMI 18.5-25). Blood was collected at 26-28 weeks' gestation, 36-40 weeks' gestation and 6-12 weeks postpartum and D-dimer concentrations and endogenous thrombin potential (ETP) were determined. Student's t-test was used to analyse differences in mean D-dimer and ETP. At 36-40 weeks, obese pregnant women had higher D-dimer concentrations (P = 0.001) but lower ETP levels compared with nonobese women (P = 0.044). D-dimer was higher in nonobese than in obese women at 6-12 weeks postpartum (P = 0.026). There was no difference in mean D-dimer (P = 0.825) and mean ETP (P = 0.424) between obese and nonobese women at 26-28 weeks. No difference was observed in mean ETP at 6-12 weeks postpartum (P = 0.472). ETP was lower in both obese and nonobese women postpartum than during pregnancy. D-dimer was lower in obese women but not in nonobese women postpartum. D-dimer concentrations and ETP were not significantly different during multiple time points in pregnancy and postpartum between obese and nonobese pregnant women suggesting limited utility in VTE risk assessment in obese pregnant women.

OBJECTIVE To examine the adverse drug reactions (ADRs) and the efficacy of intravenous iron polymaltose and ferric carboxymaltose (FCM) among gynecology/obstetric patients with anemia. METHODS The present retrospective observational study examined data from anemic obstetrics and gynecology patients who received either iron polymaltose or FCM between January 1, 2011, and April 30, 2015, at The Royal Women's Hospital, Victoria, Australia. Patient demographic data, dosage, ADR documentation, and hemoglobin levels were collected from medical records and compared. RESULTS The study included 221 patients; 111 and 110 received iron polymaltose and FCM, respectively. ADRs were documented for 18 (16.2%) patients in the iron polymaltose group and 2 (1.8%) in the FCM group (P

Background: The 2001 National Health and Medical Research Council/Australasian Society of Blood Transfusion Clinical Practice Guidelines for cryoprecipitate are being updated, and cryoprecipitate has been incorporated into new Patient Blood Management modules. Aims: This clinical audit sought to clarify current cryoprecipitate use in Victoria, Tasmania and the Australian Capital Territory; assess adherence to guidelines; and gain insights into deviations from recommended practice. This information can be utilised in updating guidelines to make them more relevant, to identify areas for clinician education and to form a baseline of practice prior to release of the 2011 guidelines. Methods: Participating institutions were invited to audit up to 30 consecutive episodes of cryoprecipitate transfusion over an 11-month period in 2008. The audits were conducted using a standardised pro forma and involved review of patient records. These were collated electronically using algorithms to determine alignment versus nonalignment with guidelines. Results: Cryoprecipitate is used in a variety of situations with surgery accounting for the highest volume. Twenty-six per cent (26%) of transfusions were aligned with 2001 guidelines rising to 61% with a modified fibrinogen trigger. Fibrinogen levels did not appear to dictate all clinical decisions regarding cryoprecipitate use perhaps owing to the acuity of many cases. Additional bleeding risk together with low fibrinogen levels (e.g. thrombocytopenic patients) may contribute to empiric cryoprecipitate use. Conclusions: These results highlight discrepancies between guidelines and practice, providing rationale for the update of the guidelines that is currently underway. Cryoprecipitate has attendant risks, and it is appropriate that transfusion be restricted to situations with good evidence or sound principles to underpin use.

Protein geranylgeranyltransferase type I (GGTase-I) is responsible for the posttranslational lipidation of CAAX proteins such as RHOA, RAC1, and cell division cycle 42 (CDC42). Inhibition of GGTase-I has been suggested as a strategy to treat cancer and a host of other diseases. Although several GGTase-I inhibitors (GGTIs) have been synthesized, they have very different properties, and the effects of GGTIs and GGTase-I deficiency are unclear. One concern is that inhibiting GGTase-I might lead to severe toxicity. In this study, we determined the effects of GGTase-I deficiency on cell viability and K-RAS-induced cancer development in mice. Inactivating the gene for the critical beta subunit of GGTase-I eliminated GGTase-I activity, disrupted the actin cytoskeleton, reduced cell migration, and blocked the proliferation of fibroblasts expressing oncogenic K-RAS. Moreover, the absence of GGTase-I activity reduced lung tumor formation, eliminated myeloproliferative phenotypes, and increased survival of mice in which expression of oncogenic K-RAS was switched on in lung cells and myeloid cells. Interestingly, several cell types remained viable in the absence of GGTase-I, and myelopoiesis appeared to function normally. These findings suggest that inhibiting GGTase-I may be a useful strategy to treat K-RAS-induced malignancies.

Pulmonary embolism is one of the leading causes of mortality in pregnancy in the Western world. No clinical prediction models have been validated in pregnancy. As a result, any pregnant woman presenting with signs possibly consistent with pulmonary embolism is investigated radiologically. This study investigates whether using clinical prediction models for pulmonary embolism in pregnancy should be pursued in future prospective trials. The aim of this study was to retrospectively evaluate the Wells clinical prediction model and ventilation-perfusion scanning for pulmonary embolism in pregnancy. A retrospective study was performed on consecutive pregnant women who presented with suspected pulmonary emboli and underwent ventilation perfusion scanning at two tertiary institutions from 2007 until 2010. The clinical pretest probability was determined as likely or unlikely by two independent clinicians retrospectively using Wells-modified criteria. Scans were determined as normal, nondiagnostic or high probability for pulmonary emboli independently by two experienced radiologists. Disagreements were resolved by a third assessor independently. In 183 pregnant women, the pretest probability was determined as 'pulmonary emboli likely' in 76 (42%) and 'pulmonary emboli unlikely' in 107 (58%) of women. Scans were of high probability in four (2%), nondiagnostic in six (3%) and normal in 173 (95%) of women. This gives the pretest probability using Wells-modified criteria a sensitivity of 100% [95% confidence interval (CI) 0.4-1.0] and a negative predictive value of 100% (95% CI 0.96-1.0). A structured clinical model such as modified Wells criteria may be useful in pregnancy, but further prospective evaluation is required.

The diagnosis and management of pulmonary embolism in pregnancy is difficult, because diagnostic procedures and the use of anticoagulants potentially can expose mother and fetus to adverse effects. This article reviews evidence for current best practice and emerging novel techniques for the diagnosis of pulmonary embolism in pregnancy and includes clinical prediction models, biomarkers, and diagnostic imaging that may offer improvement in the diagnosis and investigation of pulmonary embolism in pregnancy in the future. The usefulness of new anticoagulant agents (fondaparinux, rivaroxaban, and dabigatran) in managing pulmonary embolism in future pregnancies is also explored.

Hyperactive RAS signaling is caused by mutations in RAS genes or a deficiency of the neurofibromatosis gene (NF1) and is common in myeloid malignancies. In mice, expression of oncogenic K-RAS or inactivation of Nf1 in hematopoietic cells results in myeloproliferative disorders (MPDs) that do not progress to acute myeloid leukemia (AML). Because NF1 is a RAS-GTPase–activating protein it has been proposed that NF1 deficiency is functionally equivalent to an oncogenic RAS. It is not clear, however, whether Nf1 deficiency would be redundant in K-RAS–induced MPD development or whether the 2 mutations would cooperate in leukemogenesis. Here, we show that the simultaneous inactivation of Nf1 and expression of K-RASG12D in mouse hematopoietic cells results in AML that was fatal in primary mice within 4 weeks and transplantable to sublethally irradiated secondary recipients. The data point to a strong cooperation between Nf1 deficiency and oncogenic K-RAS.

Hyperactive signaling through the RAS proteins is involved in the pathogenesis of many forms of cancer. The RAS proteins and many other intracellular signaling proteins are either farnesylated or geranylgeranylated at a carboxyl-terminal cysteine. That isoprenylcysteine is then carboxyl methylated by isoprenylcysteine carboxyl methyltransferase (ICMT). We previously showed that inactivation of Icmt mislocalizes the RAS proteins away from the plasma membrane and blocks RAS transformation of mouse fibroblasts, suggesting that ICMT could be a therapeutic target. However, nothing is known about the impact of inhibiting ICMT on the development of malignancies in vivo. In the current study, we tested the hypothesis that inactivation of Icmt would inhibit the development or progression of a K-RAS–induced myeloproliferative disease in mice. We found that inactivating Icmt reduced splenomegaly, the number of immature myeloid cells in peripheral blood, and tissue infiltration by myeloid cells. Moreover, in the absence of Icmt, the ability of K-RAS–expressing hematopoietic cells to form colonies in methylcellulose without exogenous growth factors was reduced dramatically. Finally, inactivating Icmt reduced lung tumor development and myeloproliferation phenotypes in a mouse model of K-RAS–induced cancer. We conclude that inactivation of Icmt ameliorates phenotypes of K-RAS–induced malignancies in vivo.

The RAS proteins undergo farnesylation of a carboxyl-terminal cysteine (the “C” of the carboxyl-terminal CaaX motif). After farnesylation, the 3 amino acids downstream from the farnesyl cysteine (the -aaX of the CaaX motif) are released by RAS-converting enzyme 1 (RCE1). We previously showed that inactivation of Rce1 in mouse fibroblasts mislocalizes RAS proteins away from the plasma membrane and inhibits RAS transformation. Therefore, we hypothesized that the inactivation of Rce1 might inhibit RAS transformation in vivo. To test this hypothesis, we used Cre/loxP recombination techniques to simultaneously inactivate Rce1 and activate a latent oncogenic K-RAS allele in hematopoietic cells in mice. Normally, activation of the oncogenic K-RAS allele in hematopoietic cells leads to rapidly progressing and lethal myeloproliferative disease. Contrary to our hypothesis, the inactivation of Rce1 actually increased peripheral leukocytosis, increased the release of immature hematopoietic cells into the circulation and the infiltration of cells into liver and spleen, and caused mice to die more rapidly. Moreover, in the absence of Rce1, splenocytes and bone marrow cells expressing oncogenic K-RAS yielded more and larger colonies when grown in methylcellulose. We conclude that the inactivation of Rce1 worsens the myeloproliferative disease caused by oncogenic K-RAS.