A time-driven, activity-based costing methodology for determining the costs of red blood cell transfusion in patients with beta thalassaemia major.

OBJECTIVES: To describe the methodology to estimate the total cost of administration of a single unit of red blood cells (RBC) in adults with beta thalassaemia major in an Australian specialist haemoglobinopathy centre. BACKGROUND: Beta thalassaemia major is a genetic disorder of haemoglobin associated with multiple end-organ complications and typically requiring lifelong RBC transfusion therapy. New therapeutic agents are becoming available based on advances in understanding of the disorder and its consequences. Assessment of the true total cost of transfusion, incorporating both product and activity costs, is required in order to evaluate the benefits and costs of these new therapies. METHODS: We describe the bottom-up, time-driven, activity-based costing methodology used to develop process maps to provide a step-by-step outline of the entire transfusion pathway. Detailed flowcharts for each process are described. Direct observations and timing of the process maps document all activities, resources, staff, equipment and consumables in detail. The analysis will include costs associated with performing these processes, including resources and consumables. Sensitivity analyses will be performed to determine the impact of different staffing levels, timings and probabilities associated with performing different tasks. RESULTS: Thirty-one process maps have been developed, with over 600 individual activities requiring multiple timings. These will be used for future detailed cost analyses. CONCLUSIONS: Detailed process maps using bottom-up, time-driven, activity-based costing for determining the cost of RBC transfusion in thalassaemia major have been developed. These could be adapted for wider use to understand and compare the costs and complexities of transfusion in other settings.

A study of venous thrombosis incidence in patients with acute hyperthyroidism.

BACKGROUND: Hyperthyroidism is not a widely acknowledged risk factor for venous thrombosis (VT), such as deep vein thrombosis, pulmonary embolism and cerebral VT. Several case reports and case-control studies support an association between VT and hyperthyroidism. Prothrombotic changes in the coagulation pathway in thyrotoxic subjects include reversible elevation of factor VIII and von Willebrand factor, and give biological plausibility to the association and possibly causation for VT. AIM: We sought to determine the incidence of symptomatic VT in acute hyperthyroidism. METHODS: A retrospective review of consecutive outpatients presenting to the endocrinology clinic at our district hospitals from January 2006 to December 2008 with acute hyperthyroidism was carried out. All occurrences of objectively proven symptomatic VT (deep vein thrombosis, pulmonary embolism and cerebral vein thrombosis) in the 6 months following the diagnosis of hyperthyroidism were sought. RESULTS: Four hundred and twenty-eight patients were identified, of whom most were female (80%) and relatively young (mean age 47 years). Three patients (0.70%: 95% confidence interval 0.14-2.0%) were identified with a confirmed VT within 6 months of the diagnosis of hyperthyroidism. CONCLUSIONS: Although the literature suggests moderate association between VT and acute hyperthyroidism, our data show that the absolute risk is low. Furthermore, our data suggest that hyperthyroidism is usually an additional risk factor but rarely the sole risk factor for VT.

The clinicopathological features of thrombosis with thrombocytopenia syndrome following ChAdOx1-S (AZD1222) vaccination and case outcomes in Australia: a population-based study.

Background: Thrombosis with thrombocytopenia syndrome (TTS) associated with viral vector COVID-19 vaccines, including ChAdOx1-S (AstraZeneca AZD1222) vaccine, can result in significant morbidity and mortality. We report the clinicopathological features of TTS following ChAdOx1-S vaccination and summarise the case outcomes in Australia. Methods: In this cohort study, patients diagnosed with TTS in Australia between 23 March and 31 December 2021 were identified according to predefined criteria. Cases were included if they met the Therapeutic Goods Administration (TGA) probable and confirmed case definitions and were reclassified using Centres for Disease Control and Prevention (CDC) definition for analysis. Data were collected on patient baseline characteristics, clinicopathological features, risk factors, treatment and outcomes. Findings: A total of 170 TTS cases were identified, with most occurring after the first dose (87%) of ChAdOx1-S. The median time to symptom onset after vaccination and symptom onset to admission was 11 and 2 days respectively. The median age of cases was 66 years (interquartile range 55-74). All except two patients received therapeutic anticoagulation and 66% received intravenous immunoglobulin. Overall, 85.3% of cases were discharged home after a median hospitalisation of 6 days, 9.4% required ongoing rehabilitation and 5.3% died. Eight deaths were related to TTS, with another dying from an unrelated condition while receiving treatment for TTS. Deaths occurred more commonly in those classified as Tier 1 according to the CDC definition and were associated with more severe thrombocytopenia and disease-related haemorrhage. Interpretation: TTS, while rare, can be severe and have catastrophic outcomes in some individuals. In Australia, the mortality rate was low compared to that reported in other high-income countries. Almost all received therapeutic anticoagulation with no bleeding complications and were successfully discharged. This emphasises the importance of community education and an established pathway for early recognition, diagnosis and treatment of TTS. Funding: Australian Commonwealth Department of Health and Aged Care. H.A Tran, N. Wood, J. Buttery, N.W. Crawford, S.D. Chunilal, V.M. Chen are supported by Medical Research Future Funds (MRFF) grant ID 2015305.

How do we manage venous thromboembolism in pregnancy? A retrospective review of the practice of diagnosing and managing pregnancy-related venous thromboembolism at two major hospitals in Australia and New Zealand.

BACKGROUND: North American and European literature suggest that the incidence rate for pregnancy-related thromboembolism (VTE) ranges from 0.5 to 2 per 1000 pregnancies. However, there is a paucity of data regarding pregnancy-related VTE in Australia and New Zealand. AIMS: To define the epidemiology, management and adverse effects of pregnancy-related VTE in Australia and New Zealand. METHOD: Retrospective chart review of pregnant patients with objectively diagnosed pregnancy-related VTE at Monash Medical Centre and the North Shore Hospital from January 2007 to March 2011. RESULTS: Sixty women with VTE were identified, 31 and 29 in the antepartum and post-partum period respectively. VTE occurred as early as 8 weeks of gestation. There was a trend towards higher proportion of PE in the postpartum period. Most antenatal patients were started on enoxaparin and dosed according to weight at diagnosis. A wide variability in maintenance dosing strategies was observed. Three (5%, 95% CI: 1% to 14%) patients suffered major bleeds, all occurring post-partum. Recurrences occurred in two post-partum patients who received a truncated course of enoxaparin for distal deep-vein thrombosis. Although more women had an induction of labour, this did not translate into an increased Caesarean section rate. CONCLUSION: The epidemiology of pregnancy-related VTE is similar to that of other developed countries. All three bleeding events occurred in the immediate post-partum setting, highlighting the need for caution at this critical time. VTE recurrences occurred in those women with post-partum distal deep-vein thrombosis treated with an abbreviated course of enoxaparin.

The APTT response of pregnant plasma to unfractionated heparin.

Pregnancy is associated with a physiological increase in coagulation factors and heparin binding proteins; both can affect the activated partial thromboplastin time (APTT) in response to unfractionated heparin (UFH) invalidating the use of a non-pregnant APTT therapeutic range. We compared the anticoagulant response of UFH added in vitro to the plasma of 13 pregnant (third trimester) and 15 nonpregnant women to determine whether the measured APTT and antifactor Xa activities are lower in pregnancy. Increasing concentrations of UFH were added to platelet-poor plasma from each subject and the APTT and anti-factor Xa activity were measured. The amount of UFH which was reversibly bound and neutralised by plasma heparin binding proteins was assessed by comparing the anti-factor Xa activity before and after addition of low affinity heparin (LAH). Fibrinogen, von Willebrand factor antigen (vWF Ag) and factor VIII levels, were also measured. The APTT response, assessed by the slope of the regression line of log APTT versus added heparin concentration, was attenuated in pregnant plasma (0.76 s/U/mL versus 1.2 s/U/mL, p = 0.005) and was highly correlated to increased non-specific plasma protein binding (47% versus 35% p <0.01) and increased fibrinogen (5.1 g/L versus 2.8 g/L, p < 0.01) and factor VIII activity (2.7 U/mL versus 1.2 U/mL, p <0.01). Thus, to achieve the same heparin level, pregnant women require higher daily doses of UFH than non-pregnant women. However, if UFH dose adjustments during the third trimester are based upon a non-pregnant APTT therapeutic range, systematic overdosing of pregnant women will result, possibly increasing the risk of bleeding and osteoporosis.

Antithrombotic therapy during pregnancy.

Antithrombotic therapy is required during pregnancy for the prevention and treatment of venous and arterial thromboembolism and for the prevention of pregnancy loss in women at risk. The choice of anticoagulant for venous thromboembolism during pregnancy is limited to unfractionated heparin or low molecular weight heparin because the use of warfarin is relatively contraindicated. Much of the information surrounding the pharmacokinetics and dosing of unfractionated heparin and low molecular weight heparin obtained from non-pregnant patients has been applied to pregnant women. Whether this is appropriate in the presence of significant physiological changes in pregnancy is unclear. Specific to pregnancy and unfractionated heparin use, activated partial prothrombin time may be unreliable. In addition, the appropriate dosing of low molecular weight heparin is uncertain. Because venous thromboembolism can cause significant maternal morbidity and mortality, these important issues surrounding appropriate drug dosing of anticoagulants should be addressed.

Incidence of venous thromboembolism in different ethnic groups: a regional direct comparison study.

BACKGROUND: There are few studies that directly compare the variation in incidence of venous thromboembolism (VTE) according to ethnicity. OBJECTIVE: The aim of this study was to compare the rates of VTE, deep venous thrombosis (DVT) and pulmonary embolism (PE) among different ethnic groups. METHOD: The cases diagnosed with VTE, DVT and PE for a period between March 2004 and June 2009 were identified through the hospital-based database system. The 2006 New Zealand Census data were used to calculate the rate of diagnosis. RESULTS: The observed annual incidence of VTE during this period was 81.6 per 100000 population. The relative risks of VTE when comparing European subjects with Maori, Pacific Island and Asian subjects after age standardization were 1.98 (95% confidence interval [CI], 1.63-2.41), 3.22 (95% CI, 2.60-3.99) and 4.02 (95% CI, 3.34-4.84), respectively. Relative risks of DVT after age standardization when comparing European subjects with Maori, Pacific Island and Asian subjects, were 2.14 (95% CI, 1.72-2.66), 3.20 (95% CI, 2.46-4.17) and 4.75 (95% CI, 3.80-5.94), respectively. Indirect age standardization was used for comparison of the diagnosis of PE. The ratio between the calculated expected number of cases and the actual number of cases was 1.32 (95% CI, 0.89-1.75) for Maori subjects, 2.96 (95% CI, 1.89-4.03) for Pacific Islanders and 3.89 (95% CI, 3.00-4.78) for Asians. CONCLUSION: Europeans have a significantly higher incidence of VTE compared with Maori, Pacific Island and Asian populations.

D-dimer testing in pregnant patients: towards determining the next 'level' in the diagnosis of deep vein thrombosis.

SUMMARY BACKGROUND: The role of D-dimer in excluding deep vein thrombosis (DVT) in pregnancy is currently uncertain. We hypothesized that the specificity of sensitive D-dimer assays could be improved without compromising sensitivity by using higher D-dimer cut-off values. OBJECTIVE: To determine the test characteristics of two rapid enzyme-linked immunosorbent assays and three latex agglutination assays in pregnancy. METHOD: We recruited consecutive pregnant women who presented to participating centers with suspected DVT for the study. Symptomatic women were investigated with compression ultrasonography, and received 3 months of clinical follow-up to assess for the presence of venous thrombosis. Plasma samples for D-dimer were collected and frozen at the time of presentation. The median and mean D-dimer values for respective trimesters of pregnancy in patients with and without DVT were calculated. Receiver operating curves (ROCs) were plotted for respective assays to establish the best cut-points. The test characteristics corresponding to standard cut-points and these 'pregnancy' cut-points are presented. RESULTS: The prevalence of DVT in our cohort was 6.6% (95% confidence interval 4.0-10.6%). The mean and median D-dimer values were significantly increased throughout pregnancy. Overall, women with confirmed DVT had higher D-dimer levels than women without DVT (P < 0.0001). Improved specificities (62-79%) were observed with the use of higher cut-points obtained from ROCs for all five assays, and high sensitivities were maintained (80-100%) for DVT diagnosis. CONCLUSION: Using higher cut-points than those used in non-pregnant patients, the specificity of D-dimer assays for the diagnosis of DVT in pregnancy can be improved without compromising sensitivity. Validation in prospective management studies is needed.