Dimeric FcγR ectodomains detect pathogenic anti-platelet factor 4-heparin antibodies in heparin-induced thromobocytopenia.

Essentials FcγRIIa mediates life-threatening heparin-induced thrombocytopenia (HIT). Most anti-platelet factor (PF)4-heparin IgGs are not pathogenic so diagnosis of HIT is challenging. Dimeric rsFcγRIIa was used to quantify receptor-binding activity of anti-PF4-heparin antibodies. Dimeric rsFcγRIIa binding specifically correlated with occurrence of HIT. SUMMARY: Background Heparin-induced thrombocytopenia (HIT) is a major and potentially fatal consequence of antibodies produced against platelet factor 4 (PF4)-heparin complexes following heparin exposure. Not all anti-PF4-heparin antibodies are pathogenic, so overdiagnosis can occur, with resulting inappropriate use of alternative anticoagulation therapies that have associated risks of bleeding. However, definitive platelet functional assays are not widely available for routine analysis. Objectives To assess the utility of dimeric recombinant soluble FcγRIIa (rsFcγRIIa) ectodomains for detecting HIT antibodies. Patients/Methods Plasma from 27 suspected HIT patients were tested for pathogenic anti-PF4-heparin antibodies by binding of a novel dimeric FcγRIIa ectodomain probe. Plasmas were also tested by the use of PF4-heparin IgG ELISA, the HemosIL AcuStar HIT IgG-specific assay, and a serotonin release assay (SRA). Results The dimeric rsFcγRIIa test produced no false positives and excluded four samples that were positive by IgG ELISA. In this small patient cohort, the novel assay correctly assigned 93% of the suspected HIT patients, with two of the HIT patients being scored as false negatives. The improved discrimination of the novel assay over the IgG ELISA, which scored four false positives, supports the mechanistic interpretation that binding of dimeric rsFcγRIIa detects pairs of closely spaced IgG antibodies in PF4-heparin immune complexes. Conclusions This study found the cell-free, function-based dimeric rsFcγRIIa assay to be convenient, simple, and potentially predictive of HIT. The assay had improved specificity over the IgG ELISA, and correlated strongly with the AcuStar HIT IgG-specific assay, warranting further evaluation of its potential to identify HIT in larger patient cohorts.

Australian multicentre study of current real-world prophylaxis practice in severe and moderate haemophilia A and B.

INTRODUCTION: With the emergence of novel treatment products for haemophilia and an increasing focus on the benefits of pharmacokinetic driven individualized prophylaxis, robust national data with regard to current patterns of factor consumption and adherence are required. AIM: To characterize current Australian practice with regard to use of prophylactic clotting factor infusions in patients with moderate or severe haemophilia A (HA) and haemophilia B (HB). METHODS: This was a retrospective, non-interventional study utilizing Australian Bleeding Disorder Registry (ABDR) data collected over a 12 month period. Registered and consented patients with moderate or severe HA or HB without inhibitors were included. RESULTS: A total of 718 HA (551 severe, 167 moderate) and 166 HB (87 severe, 79 moderate) patients were included. Regular prophylaxis was prescribed in 453 patients (82%) with severe HA, 42 patients (25%) with moderate HA, 66 patients (75%) with severe HB and 11 patients (14%) with moderate HB. Near universal prophylaxis was achieved in the paediatric subgroup. The mean weekly dose of factor VIII in severe HA was 84 international units/kg/wk (IU/kg/wk) vs 71 IU/kg/wk of factor IX in severe HB. Most patients on prophylaxis were treated ≥3 times/wk (HA) or 2 times/wk (HB). Non-adherence peaked in the 20-29 year age group. Older individuals on regular prophylaxis used more factor than was expected for their prescribed regimen. CONCLUSION: Prophylaxis rates in severe haemophilia are comparable with other developed nations. The benefit of a national registry is demonstrable. Furthermore research into the underlying reasons for non-compliance in young adults with haemophilia is required.

Comparison of von Willebrand factor (VWF) activity levels determined by HemosIL AcuStar assay and HemosIL LIA assay with ristocetin cofactor assay by aggregometry.

INTRODUCTION: Diagnosis of von Willebrand disease (VWD) requires quantitative as well as qualitative determination of von Willebrand factor (VWF) levels. For functional assessment of VWF, ristocetin cofactor assay by aggregometry is considered to be the gold standard. However, need for technical expertise, labour intensiveness, difficult standardization and high intra- and inter- assay variabilities are some of the limitations of this methodology. Various assays for determination of VWF adhesive function using different methodologies have been developed in recent years. AIM: To evaluate the HemosIL AcuStar chemiluminescence assay (VWF:RCo[Acu]) and the HemosIL latex immunoassay (VWF:act) as diagnostic tests for VWD and identification of type 2 VWD in comparison with the ristocetin cofactor assay performed by aggregometry (VWF:RCo[Agg]). METHODS: Results from 96 samples analysed by VWF:RCo[Acu] and 128 samples by VWF:act were compared with VWF:RCo[Agg]. Sixty of these samples (25 normal, 17 type 1 and 18 type 2) were analysed by all three assays. RESULTS: VWF:RCo[Acu] showed excellent agreement with VWF:RCo[Agg], and readily identified all type 2 VWD samples tested. VWF:act showed reasonable agreement with VWF:RCo[Agg] for most patients, but had a slightly lower sensitivity for detection of type 2 VWD. CONCLUSION: VWF:RCo[Acu] assay has the potential to replace VWF:RCo[Agg] for the diagnosis of VWD.

Thalidomide in angiodysplasia-related bleeding.

Gastrointestinal haemorrhage from angiodysplastic lesions is not only difficult to identify, but often refractory to endoscopic intervention. Patients often require substantial transfusion support. Thalidomide has emerged as a promising medical strategy in angiodysplasia-related bleeding. We present our experience and report the findings from a review of the literature. Despite its side-effect profile, thalidomide remains the therapeutic modality with the best evidence in this difficult clinical scenario.

Challenges in hemophilia care in Australia and New Zealand.

BACKGROUND: Health and life expectancy for people with hemophilia have improved significantly in recent years, but we face new challenges, especially in the context of resource-constrained health services. AIM: This paper aims to highlight such challenges and propose practical solutions. METHODS: Nine hemophilia specialists from Australia and New Zealand reached consensus on areas of greatest need for improvement in hemophilia care in these countries, based on clinical experience and published data, and agreed on how to address these. RESULTS: Demography, optimizing treatment and assessing treatment success were identified as broad areas of challenge which included: comorbidities in ageing patients; transitioning from pediatric to adult care; equity of care for remote populations; weight-based dosing in obese patients; tailoring prophylaxis; accurate diagnosis of acute joint pain; managing chronic arthropathy; providing psychosocial support; consistency in definitions and assessment; and quantifiable outcome measures. Practice points included increased cross-specialty coordination and including psychologists and rheumatologists as part of comprehensive care teams; close collaboration between pediatric and adult centers to facilitate transition of care; systems such as telehealth that ensure continuity of care for remote populations; using pharmacokinetic data to tailor therapy; rapid and accurate diagnosis of acute joint pain; using data from bleeding registries to assess treatment effects and help with service planning; and ensuring consistency through benchmarking and standardization of HTCs. SUMMARY: Achieving treatment equity, optimal outcomes and cost savings may be possible through investing in national governance structures, expanding the comprehensive model of care and implementing innovative solutions tailored to local needs.

New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Australasian Society of Thrombosis and Haemostasis.

New oral anticoagulants (NOAC) are becoming available as alternatives to warfarin to prevent systemic embolism in patients with non-valvular atrial fibrillation and for the treatment and prevention of venous thromboembolism. An in-depth understanding of their pharmacology is invaluable for appropriate prescription and optimal management of patients receiving these drugs should unexpected complications (such as bleeding) occur, or the patient requires urgent surgery. The Australasian Society of Thrombosis and Haemostasis has set out to inform physicians on the use of the different NOAC based on current available evidence focusing on: (i) selection of the most suitable patient groups to receive NOAC, (ii) laboratory measurements of NOAC in appropriate circumstances and (iii) management of patients taking NOAC in the perioperative period, and strategies to manage bleeding complications or 'reverse' the anticoagulant effects for urgent invasive procedures.

Safety and sensitivity of two ultrasound strategies in patients with clinically suspected deep venous thrombosis: a prospective management study.

BACKGROUND: It remains unclear whether a single complete ultrasound examination, which detects calf vein thrombosis, is as safe as a baseline rapid ultrasound examination, repeated after 1 week when negative, which examines the veins in the groin and the knee. Therefore, we compared the safety and feasibility of two diagnostic ultrasound strategies, involving rapid and complete compression ultrasound (CUS) examination. METHODS: Consecutive patients with suspected deep vein thrombosis (DVT) underwent clinical probability assessment. In patients with an unlikely clinical probability and a normal D-dimer finding, DVT was considered to be excluded. All others were randomized to undergo a rapid or a single complete CUS examination. Patients in whom DVT was excluded were followed for 3 months to assess the incidence of venous thromboembolism (VTE). RESULTS: A total of 1002 patients were included. A clinical decision rule indicating DVT to be unlikely and a normal D-dimer finding occurred in 481 patients (48%), with a VTE incidence of 0.4% [95% confidence interval (CI) 0.05-1.5%] during follow-up. DVT was confirmed in 59 of the 257 patients (23%) who underwent rapid CUS examination, and in 99 of the 264 patients (38%) who underwent complete CUS examination. VTE during follow-up occurred in four patients (2.0%; 95% CI 0.6-5.1%) in the rapid CUS arm, and in two patients (1.2%; 95% CI 0.2-4.3%) in the complete CUS arm. CONCLUSIONS: A diagnostic strategy with a clinical decision rule, a D-dimer test and a CUS examination is safe and efficient. Both the rapid and the complete CUS test are comparable and efficient strategies, with differing advantages and disadvantages.

Vehicle-controlled, randomized, double-blind study to assess safety and efficacy of imiquimod 5% cream applied once daily 3 days per week in one or two courses of treatment of actinic keratoses on the head.

BACKGROUND: Imiquimod has been investigated as a safe and effective therapeutic option for the treatment of actinic keratosis (AK). OBJECTIVES: To evaluate imiquimod vs. vehicle applied three times a week for 4 weeks in one or two courses of treatment for AK on the face or balding scalp. PATIENTS AND METHODS: Patients diagnosed with AK were enrolled in this multicentre, vehicle-controlled, double-blind study conducted in Europe. Twenty study centres enrolled a total of 259 patients in this study. Patients applied the study drug for 4 weeks, entered a 4-week rest period and if they did not have complete clearance, they then entered a second course of treatment. RESULTS: Patients in the imiquimod group had an overall complete clearance rate of 55.0% (71/129) vs. a rate of 2.3% (3/130) for the vehicle group. There was a high rate of agreement between the clinical assessment and histological findings with respect to AK lesion clearance. At both 8-week post-treatment visits, the negative predictive value of the investigator assessment was 92.2% for clinical assessments vs. histological results. CONCLUSIONS: A 4-week course of treatment with three times weekly dosing of imiquimod 5% cream, with a repeated course of treatment for those patients who fail to clear after the first course of treatment, is a safe and effective treatment for AK. The overall complete clearance rate (complete clearance after either course 1 or course 2) is comparable to the 16-week treatment regimen, while decreasing drug exposure to the patient and decreasing the overall treatment time.

Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from a randomized vehicle-controlled phase III study in Europe.

BACKGROUND: Imiquimod is an immune response modifier that acts through toll-like receptor 7 to induce cytokine production and a subsequent innate and adaptive cell-mediated immune response. Clinical studies have demonstrated clinical and histological clearance of superficial basal cell carcinoma (sBCC) after treatment with imiquimod 5% cream. OBJECTIVES: To evaluate the safety and clinical efficacy of imiquimod (Aldaratrade mark; 3M Pharmaceuticals, St Paul, MN, U.S.A.) 5% cream for the treatment of sBCC in a multicentre, randomized, parallel, vehicle-controlled, double-blind, phase III clinical study conducted at 26 centres in Europe. METHODS: Subjects who had at least one histologically confirmed sBCC tumour were randomized to apply imiquimod or vehicle cream to the target tumour once daily, seven times per week (7 x/week) for 6 weeks. The target tumour location was identified with an indelible ink mark before treatment initiation. The treated tumour site was clinically assessed for treatment response at 12 weeks post-treatment and was then excised for histological evaluation. Efficacy assessments included the composite response rates (proportion of subjects with clinical and histological clearance) and response rates solely based on histology (proportion of subjects with histological clearance). Safety assessments, which included adverse events and scoring of local skin reactions (LSRs), were carried out throughout the study. RESULTS: In total, 166 subjects were enrolled in this study. For the intent-to-treat dataset, there was a statistically significant difference between imiquimod and vehicle groups for both composite clearance rates (clinical and histological assessments) and histological clearance rates. Composite clearance was demonstrated in 77% and 6% of subjects treated with imiquimod and vehicle cream, respectively. Histological clearance was demonstrated in 80% and 6% of subjects treated with imiquimod and vehicle cream, respectively. The most frequently reported safety findings were investigator-assessed LSRs and spontaneous reports by subjects of application site reactions, which occurred more frequently in the imiquimod group than in the vehicle group. CONCLUSIONS: Imiquimod 5% cream administered 7 x/week for 6 weeks is a safe and effective treatment for sBCC when compared with vehicle cream.

Palliative care on Manitoulin Island. Views of family caregivers in remote communities.

OBJECTIVE: To describe family caregivers' experiences with palliative care services in rural communities. DESIGN: Qualitative study. SETTING: Manitoulin Island, Ont. PARTICIPANTS: Thirteen family caregivers of 12 deceased patients who had received palliative care services. METHOD: Twenty-five family caregivers were recruited by mail and local newspaper. Eight were excluded because they lived off the Island or were too recently bereaved; one declined an interview; and three were excluded by researchers. Initial contact was by telephone; those retained (13 people) were interviewed at home. Interviews were conducted by the same researcher using a semistructured interview guide. All interviews were audiotaped and transcribed, and content was analyzed. MAIN FINDINGS: Three interwoven themes were identified: access to services, quality of services, and support and caring. Hospital and community-based services were accessed with ease at the local level; difficulties were noted when accessing services in tertiary care centres. Participants were generally grateful for and pleased with services received. Two areas of concern raised by participants were communication and pain and symptom control. Participants suggested to the Ministry of Health ways to improve rural palliative care services. More public funding for in-home palliative care services was identified as a priority. CONCLUSION: Participants thought good services and supportive care at the local level made up for difficulties in accessing and using palliative services in tertiary care centres. Community spirit and culture were seen as making situations more bearable.

Temporal patterns of veterans' psychiatric service utilization, disability payments, and cocaine use.

This study examined temporal patterns of service utilization, disability benefits, and substance use. Specifically, it investigated whether the first day of the first week of each month (when disability payments are disbursed) was associated with increased emergency room (ER) use and more frequent cocaine use among psychiatric patients. All 1993 psychiatric ER presentations (n=1,448) at a Veterans Administration hospital were reviewed in order by the week of each month in which they occurred. A random subsample of only those admitted to an inpatient psychiatric service (n=143) was further assessed for amount of disability payments received and recent cocaine use. This study found that for the total population of patients utilizing the ER, most ER visits occurred during the first week, followed by weeks two, three, and four respectively. The highest percentage (49%) of patients who used cocaine were those admitted during the first week of the month, followed by week two (39%), week four (28%) and week three (25%). For the subsample of patients admitted to inpatient services, patients hospitalized during the fourth week of the month were those receiving the highest disability payments. This study found that cocaine users have the most ER visits during the first week of the month following receipt of benefits. Current data, if confirmed, would suggest public policy changes, such as payment of entitlement money to cocaine users through a third-party payee and stipulated treatment for psychiatric patients with substance use disorders as a condition of payment. Ethical and political issues, including confidentiality and patient autonomy, would need to be considered in any such policy changes.

Cytologic diagnosis of a primary pure oat cell carcinoma of the bladder in voided urine. A case report.

BACKGROUND: The urinary bladder is an uncommon site for primary oat cell carcinoma, with as few as 30 histologically diagnosed cases described in the literature. The first reported cytologic diagnosis was made in 1991. CASE: A 76-year-old female presented with gross hematuria. Voided urine cytology showed small, dark cells with little visible cytoplasm and coarse chromatin. Subsequent histopathologic, immunopathologic and electron microscopic studies confirmed the diagnosis of primary oat cell carcinoma. CONCLUSION: The diagnosis of oat cell carcinoma is well recognized in respiratory cytology. The same cells found in a urinary specimen may suggest a primary oat cell tumor in conjunction with negative clinical and radiologic investigations for a primary tumor elsewhere.

Underdiagnosis of PTSD and substance use disorders in hospitalized female veterans.

Discharge diagnoses of 31 female veterans and 31 male veterans hospitalized at a large urban VA medical center were examined to elucidate possible biases in clinicians' diagnostic practices. Only one woman in the sample was diagnosed as having posttraumatic stress disorder, compared with seven men. All men given this diagnosis were combat veterans. Although about half of each group had a drug-positive urine screen on admission, only 11 women received a diagnosis of a substance use disorder, compared with 24 men. VA clinicians may need further training and experience assessing the presentation of PTSD and substance use disorders in women.

Household and labour market change: implications for the growth of inequality in Britain.

The paper examines the relationships between population and household change, on the one hand, and labour market/employment change, on the other, and considers how these relationships have contributed to the growth of inequality. The perspective of the paper is sociological, although much of the work done in these areas has been carried out by demographers and economists. Areas where sociological research remains to be done are highlighted. Developments in patterns of fertility and in households are linked to the growth of individualism and to changes in the labour market, and shown to be implicated jointly in the marked growth of inequality in Britain. The paper argues that future research must link households and labour markets, and work towards understanding emerging new relationships between working and private lives, between living arrangements and labour supply, and between individual freedom and social integration.