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.

The use of a co-design model in improving timely bleed reporting by adults with haemophilia living in the Auckland region of New Zealand.

Many adult patients diagnosed with phenotypically moderate and severe haemophilia living in the Auckland region of New Zealand do not report bleeding episodes within a timeframe that allows for optimal assessment and management. This can result in poor clinical outcomes for patients and poor oversight of the use of expensive clotting factor concentrates. Our goal was to improve both the number and speed at which bleeding episodes were reported to our centre, improving access to care and clinical oversight of the use of expensive factor concentrates and aiding the development of a care partnership with patients. We worked with 70 adult PWH living in the Auckland region of New Zealand with moderate and severe haemophilia A and B. Over a 5-month period between March and July 2013 we used a co-design model to develop and implement a range of strategies to improve the timing and frequency of bleed reporting. Mean bleed reporting time was reduced threefold, with a threefold increase in the number of bleeds reported per month. We reduced the number of bleeding episodes reported outside of a prespecified 48-h time limit by 68%. We significantly improved bleed reporting and time to report, indicating improved access to our services, improved clinical oversight and improved accountability to our national funder. We have achieved a care partnership and a reduction in factor consumption for the study population without compromising the quality of care they receive.

How we use recombinant activated Factor VII in patients with haemophilia A or B complicated by inhibitors. Working group of hematology experts from Australia and New Zealand, Melbourne, April 2011.

The management of bleeds in patients with haemophilia A or B complicated by inhibitors is complex. Recombinant activated Factor VII (rFVIIa; NovoSeven RT) is an established therapy in these patients. To develop a consensus-based guide on the practical usage of rFVIIa in haemophilia complicated by inhibitors, nine expert haemophilia specialists from Australia and New Zealand developed practice points on the usage of rFVIIa, based on their experience and supported by published data. Practice points were developed for 13 key topics: control of acute bleeding; prophylaxis; surgical prophylaxis; control of breakthrough bleeding during surgery or treatment of acute bleeds; paediatric use; use in elderly; intracranial haemorrhage; immune tolerance induction; difficult bleeds; clinical monitoring of therapy; laboratory monitoring of therapy; concomitant antifibrinolytic medication; practical dosing. Access to home therapy with rFVIIa is important in allowing patients to administer treatment early in bleed management. In adults, 90-120 µg/kg is the favoured starting dose in most settings. Initial dosing using 90-180 µg/kg is recommended for children due to the effect of age on the pharmacokinetics of rFVIIa. In the management of acute bleeds, 2-hourly dosing is appropriate until bleeding is controlled, with concomitant antifibrinolytic medication unless contraindicated. The practice points provide guidance on the usage of rFVIIa for all clinicians involved in the management of haemophilia complicated by inhibitors.

Survival in patients with malignancy and venous thromboembolism by tumour subtype and thrombus location.

BACKGROUND: Although the association between malignancy and venous thromboembolism (VTE) is firmly established, less is known about the survival following VTE among different malignant subtypes. AIMS: We sought to estimate survival from first VTE in consecutive patients with known malignancy receiving extended low molecular weight heparin therapy. METHODS: Five hundred and fifty-nine consecutive patients presenting to the Thrombosis Unit Registry at Auckland City Hospital between January 1997 and October 2006 were observed. Events were confirmed by standard imaging procedures. The diagnosis date and site of VTE as well as the type of malignancy were recorded. RESULTS: Mean follow up was 21.4 months. Overall median survival from VTE was 13.5 months. Six-month, one-, two- and five-year survivals were 64%, 53%, 43% and 33% respectively. Survival was longest for haematological malignancy at 44.4 months, followed by prostate, bowel, breast (metastatic breast), lung and pancreatic malignancy at 29.4, 27.4, 15.5 (6.2), 2.4 and 1.9 months respectively. Median survival varied with thrombotic location from 31.1 months for upper limb/jugular deep vein thrombosis reducing to only 10.1 months for iliocaval/abdominal deep vein thrombosis, but this did not reach statistical significance. Survival from cancer diagnosis was also determined. DISCUSSION: The 1-year 53% survival in cancer patients with VTE treated using extended low molecular weight heparin is longer than that reported from large registry and population studies in which specific patient information and therapeutic regimens are unknown. Survival is critically determined by tumour type and correlates with tumour stage in women with breast cancer. There is also a trend towards differing survival by thrombus location.

D-dimer concentration increases with age reducing the clinical value of the D-dimer assay in the elderly.

BACKGROUND: The D-dimer assay is used as an exclusion test in the assessment of suspected venous thromboembolic disease; patients with a negative result have a low probability of thrombosis. We reviewed the D-dimer results from a hospital and community laboratory using the vidas D-dimer test to assess the influence of age on the D-dimer assay. METHODS: D-dimer results from 6631 unselected patients aged more than 16 years were analysed in four age groups and it was shown that the median D-dimer concentration increased with age (16-40 years, 294 ng/mL; 40-60 years, 387 ng/mL; 60-80 years; 854 ng/mL; >80 years, 1397 ng/mL). To test the effect of age on the assay specificity, a cohort of 1897 patients with suspected venous thromboembolic disease was analysed separately. Patients with a negative D-dimer were discharged without further investigation. Patients with a positive result and a clinical suspicion of thrombosis underwent further investigation. One hundred and sixty-five deep vein thrombosis or pulmonary embolus cases were identified. RESULTS: The assay specificity decreased with age from 70% in patients less than 40 years to below 5% in patients more than 80 years. Receiver operator curves were prepared for each age group and the effect of altering the threshold value was analysed. In patients 60-80 years old a threshold value of 1000 ng/mL increased assay specificity to 55% without loss of assay sensitivity. CONCLUSION: The vidas D-dimer assay with a threshold value of 500 ng/mL has little clinical value as an exclusion test in patients more than 80 years old. The assay specificity is poor (26%) in patients aged 60-80 years but could be improved by increasing the threshold value to 1000 ng/mL. We believe that this should be tested in a prospective trial.

Post-treatment residual thrombus increases the risk of recurrent deep vein thrombosis and mortality.

BACKGROUND: Recurrent thromboembolic events after an initial deep vein thrombosis (DVT) are relatively frequent. Residual thrombus in the affected veins on ultrasound scan at the completion of anticoagulant therapy has been described as a recurrence risk factor, and may have utility in stratifying those patients at risk. OBJECTIVES: The aims of the study were to correlate the risk of recurrence of DVT with the results of ultrasound at completion of oral anticoagulant therapy. A secondary aim was to review the mortality in this population. PATIENTS: A cohort of 316 DVT patients was included. The patients were divided into those with completely clear vessels on follow-up scan (45%) and those with residual thrombus identified (55%). RESULTS: The cumulative incidence of recurrence was 10% by 2 years and 23% by 5 years. Patients with residual thrombus on follow-up ultrasound were at higher risk of recurrence (hazard ratio [HR] 2.2, 1.19-4.21; P = 0.012) which remained significant after multivariate adjustment for age, gender and malignancy (HR 2.2, 1.15-4.17; P = 0.018). During follow-up, the cumulative mortality was 12% at 2 years and 27% by 5 years. The risk of death was increased in patients with residual thrombus on follow-up scan (HR 3.9, 1.93-7.71; P < 0.001) and this risk persisted after multivariate analysis of age, gender and malignancy (2.8, 1.37-5.72; P = 0.005). The majority of deaths were due to malignancy (68%) however 10 (18%) died from vascular causes. There was a trend towards increased vascular death in the patients with residual thrombus on follow-up ultrasound scan, which did not reach significance (HR 4.1, 0.87-19.33; P = 0.13). CONCLUSIONS: Consistent with previous cohort studies, recurrence risk is increased in patients with residual thrombus on ultrasound. The increased risk of death in patients with residual thrombus, with a trend towards increased vascular death, may suggest that failure of thrombus resolution is a marker of more global vascular dysfunction.

Audit of community-based anticoagulant monitoring in patients with thromboembolic disease: is frequent testing necessary?

Oral anticoagulant monitoring is managed by general practitioners in Auckland. An audit of this service in 452 patients demonstrated that anticoagulant control was in line with recommended international guidelines, with 58.3% of international normalized ratio (INR) measurements in the therapeutic range. However, the frequency of testing was high, with the majority of patients (68%), including those on long-term treatment, having INR measurements at weekly intervals. We question the need for such frequent INR testing.

The influences of obesity and glycemic control on endothelial activation in patients with type 2 diabetes.

The aims of this study were to elucidate the factors that contribute to endothelial activation and fibrinolytic abnormalities in patients with poorly controlled type 2 diabetes and to determine whether improved glycemic control reduces endothelial activation. Adhesion molecules [E-selectin, intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1], von Willebrand factor, total nitric oxide (NO), endothelin-1, tissue plasminogen activator, and plasminogen activator inhibitor-1 were measured in 43 type 2 diabetic subjects with hemoglobin A1c of 9.0% or more at baseline (compared with 21 healthy controls) who after 20 wk had been randomized to either improved (IC) or usual (UC) glycemic control. At baseline, type 2 diabetic patients had significant endothelial activation and abnormal fibrinolysis compared with control subjects. Body mass index in the diabetic patients was the only independent predictor of E-selectin (P = 0.007), ICAM-1 (P = 0.01), and NO (P = 0.008) concentrations, but not vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, or tissue plasminogen activator (all P > 0.05). Type 2 diabetic patients with a body mass index of 28 kg/m2 or less had concentrations of E-selectin, ICAM-1, endothelin-1, and NO similar to those in healthy controls. After 20 wk, hemoglobin A1c was significantly lower in IC vs. UC (IC, 8.02 +/- 0.25%; UC, 10.23 +/- 0.23%; P < 0.0001), but there were no significant changes in markers of endothelial activation or indexes of fibrinolysis. Obesity appears to be the most important predictor of endothelial activation in patients with type 2 diabetes. Short-term improvement in glycemic control does not appear to reduce endothelial activation.

Consensus guidelines for warfarin therapy. Recommendations from the Australasian Society of Thrombosis and Haemostasis.

The anticoagulant effect of warfarin should be kept at an international normalised ratio (INR) of about 2.5 (desirable range, 2.0-3.0), although a higher level may be better in a few clinical conditions. The risk of bleeding increases exponentially with INR and becomes clinically unacceptable once the INR exceeds 5.0. Warfarin therapy should be continued for around six weeks for symptomatic calf vein thrombosis, and for 3-6 months after proximal deep vein thrombosis (DVT) that occurs after surgery or limited medical illness. Therapy for six months or longer could be considered for DVT occurring without an obvious precipitating factor, proven recurrent venous thromboembolism (VTE), or if there are continuing risk factors. Oral anticoagulants prevent ischaemic stroke in atrial fibrillation (AF). Maximum efficacy requires an INR > 2.0, but some benefit remains at an INR of 1.5-1.9. Patients aged over 75 years are at greatest risk of intracranial bleeding during warfarin therapy for AF, and the target INR may be reduced to 2.0-2.5, or perhaps as low as 1.5-2.0, in such patients. Warfarin should be withheld if it is more likely to cause major bleeding than to protect from stroke (e.g., in young people with isolated AF where the annual baseline risk of stroke is < 1%). In patients with AF, aspirin is less effective than warfarin (much less effective after such patients have had a stroke or transient cerebral ischaemia). In people with prosthetic heart valves, an INR of 2.5-3.5 is probably sufficient for bileaflet or tilting disc valves, but a higher target INR is necessary for caged ball or caged disc valves. The addition of aspirin (100 mg/day) further decreases the risk of embolism but increases the risk of gastrointestinal bleeding.

The use of central venous catheters (portacaths) in children with haemophilia.

The experience with central venous implantable devices (portacaths) has been reviewed in children attending the Auckland Hospital Haemophilia Centre. Fourteen children had 23 portacaths inserted. Thirteen had severe Haemophilia A, of whom five had high responding inhibitors to factor VIII. All the children were HIV negative. Ages ranged from 4 months to 13 years at the time of initial placement and 12 were under 5 years. Indications for portacath placement included primary and secondary prophylaxis, induction of immune tolerance, prophylactic therapy post intracranial haemorrhage and poor venous access. Catheter-related infections occurred in 48% of cases. Staphylococcal species were the most common organisms isolated followed by gram-negative bacilli. 63% of the infections were successfully cleared with antibiotics. Haematoma formation occurred in 17% of catheters, primarily in patients who had high factor VIII inhibitor levels. Mechanical problems including blockage, leakage and extrusion of the portacath occurred less frequently (13%). The significant rate of infection in this immunocompetent population is consistent with other reports. Despite the obvious benefits of portacaths this complication is potentially serious and causes appreciable morbidity. In contrast, bleeding complication rates were relatively low.

Defective fibrinogen polymerization associated with a novel gamma279Ala-->Asp mutation.

A woman with menorrhagia was investigated for a suspected fibrinogen mutation when coagulation tests revealed prolonged thrombin (55 s) and reptilase (43 s) times together with a functional and an antigenic fibrinogen concentration of 0.7 and 2.8 mg/ml respectively. Heterozygosity for a gamma-chain mutation was suggested by a doublet gamma band on SDS-PAGE and an increased negative charge was observed on isoelectric focusing of HPLC-isolated gamma-chains. Electrospray ionization mass spectrometry revealed a gamma-chain mass of 48 411 Da, which was 20 Da more than the control value of 48 391 Da. Because the normal and variant gamma-chains were not resolved, this implied a 40-Da increase in 50% of the gamma-molecules. An increased negative charge and a 44-Da increase in mass was verified when DNA sequencing showed heterozygosity for an Ala (GCC)-->Asp (GAC) substitution at codon 279 of the gamma-gene. Fibrin polymerization curves indicated a delay in the onset, and a decrease in the rate, of polymerization. Examination of crystal structures showed that the adjacent Tyr-gamma280 side chain is involved in bonding across the D-D interface, and from the proximity of the gamma279Ala-->Asp mutation it would appear that this perturbs the end-to-end DD interactions between fibrin units of the growing polymer.

Screening for a prothrombotic diathesis in patients attending family planning clinics.

AIMS: 1. To determine the frequency of prothrombotic markers in young women seeking a new or a repeat prescription of the oral contraceptive pill and perceived to be at high risk of thrombosis. 2. To assess cost-effectiveness of thrombophilia testing within this population. 3. To determine the frequency of acquired activated protein C (APC) resistance. METHODS: Results of thrombophilia testing were retrospectively reviewed on 220 consecutively referred patients' plasmas. Women tested were clients attending local family planning clinics for a new or repeat contraceptive prescription. Samples for testing were collected by the Community Laboratory Service. Investigations included: antithrombin III (AT III), protein C, protein S, APC resistance, factor V Leiden mutation analysis and anti-cardiolipin antibodies. RESULTS: Abnormalities were detected in 35 (15.9%) of the 220 women tested. No patient had all tests performed. The most frequently detected abnormality was an increased APC resistance in 6.8% of the women tested. Three of the 13 patients with an abnormal APC resistance had a discrepancy between the low APC ratio and a negative mutation analysis result for factor V Leiden, suggesting acquired APC resistance. Deficiency of protein C was found in 1.2% (of 162), protein S in 2.0% (of 140), antithrombin III in 0.6% (of 159). Low-titre anti-cardiolipin antibodies were detected in 13.9% of this group (115 tested). CONCLUSIONS: The frequency of abnormal thrombophilia markers detected in this cohort of young women is not significantly different from that seen in a control population. This low incidence suggests that testing has been applied on a population screening basis, rather than preselecting a high-risk group. Thrombophilia screening in this patient group cannot be justified when the clinically relevant end-point is death from pulmonary embolism. The cost of preventing one fatal pulmonary embolism arising as a consequence of screening for activated protein C resistance due to the commonly occurring factor V Leiden is a minimum $25,000,000. This compares very unfavourably with the estimated cost per life saved in the National Breast Screening Programme.

A 20.7 kb deletion within the factor VIII gene associated with LINE-1 element insertion.

Large deletions within the factor VIII gene account for approximately 5% of the mutations causing haemophilia A. The characterization of such mutations can provide insights into the molecular mechanisms of these and other deletions in man. We have analyzed a 20.7 kb deletion spanning exons 15 to 20 within the factor VIII gene in a patient with severe haemophilia A. Long range PCR was used to investigate the extent of the deletion and to provide a template for sequencing across the deletion breakpoint. A 38-base insertion homologous to the 3' region of a LINE-1 (L1) element was detected at the breakpoint of the deletion. Normal sequence at the 5' breakpoint in intron 14 was homologous to an L1 flanking region and normal sequence at the 3' breakpoint in intron 20 was homologous to an adjacent sequence within the same L1 flanking region. A molecular mechanism for the deletion involving retrotransposition of a readthrough product of an L1 element plus its 3' flanking region is suggested.

Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group.

BACKGROUND: An intravenous course of standard (unfractionated) heparin with the dose adjusted to prolong the activated partial-thromboplastin time to a desired length is the standard initial in-hospital treatment for patients with deep-vein thrombosis, but fixed-dose subcutaneous low-molecular-weight heparin appears to be as effective and safe. Because the latter treatment can be given on an outpatient basis, we compared the two treatments in symptomatic outpatients with proximal-vein thrombosis but no signs of pulmonary embolism. METHODS: We randomly assigned patients to adjusted-dose intravenous standard heparin administered in the hospital (198 patients) or fixed-dose subcutaneous low-molecular-weight heparin administered at home, when feasible (202 patients). We compared the treatments with respect to recurrent venous thromboembolism, major bleeding, quality of life, and costs. RESULTS: Seventeen of the 198 patients who received standard heparin (8.6 percent) and 14 of the 202 patients who received low-molecular-weight heparin (6.9 percent) had recurrent thromboembolism (difference, 1.7 percentage points; 95 percent confidence interval, -3.6 to 6.9). Major bleeding occurred in four patients assigned to standard heparin (2.0 percent) and one patient assigned to low-molecular-weight heparin (0.5 percent; difference, 1.5 percentage points; 95 percent confidence interval, -0.7 to 2.7). Quality of life improved in both groups. Physical activity and social functioning were better in the patients assigned to low-molecular-weight heparin. Among the patients in that group, 35 percent were never admitted to the hospital at all, and 40 percent were discharged early. This treatment was associated with a mean reduction in hospital days of 67 percent, ranging from 29 percent to 86 percent in the various study centers. CONCLUSIONS: In patients with proximal-vein thrombosis, treatment with low-molecular-weight heparin at home is feasible, effective, and safe.

Transformation of essential thrombocythaemia to T cell acute lymphoblastic leukaemia.

Leukaemic transformation of essential thrombocythaemia is a rare event and is usually associated with previous treatment with either alkylating agents or radioactive phosphorous. We describe a patient with essential thrombocythaemia who developed an acute leukaemia of T cell phenotype following hydroxyurea therapy. The T cell phenotype of the blasts suggests the target cell for leukaemic transformation was a pluripotential stem cell.

Experience with recombinant factor VIIa in Australia and New Zealand.

Recombinant factor VIIa (rFVIIa; NovoSeventrademark) was availablefor compassionate use in Australia and New Zealand from 1991 to 1994. Over this period there were 18 treatment episodes in 9 patients, age 8-66 years, with haemophilia A and high titre inhibitors cross-reacting with porcine factor VIII. There were no significant adverse effects. Treatment with rFVIIa resulted in a successful outcome in 8 potentially life-threatening (retroperitoneal, subdural, gastro-intestinal) bleeds. Elective cystoscopy, repair of a cranial flap, yttrium synovectomy and inguinal herniotomy were performed successfully, as was surgical decompression of a flexor pollicis longus bleed. Treatment of a patient with an infected haematoma had limited success, attributed to intermittent suboptimal doses. In 2 patients, satisfactory haemostasis was achieved for multiple dental extractions; subsequent oozing was attributed to suboptimal rFVIIa and/or antifibrinolytic therapy.

Factor IX gene mutations in haemophilia B: a New Zealand population-based study.

Haemophilia B (Christmas disease) is an X-linked bleeding disorder resulting from an inherited deficiency of coagulation factor IX activity. Due to the heterogeneity of mutations within the factor IX gene there is a marked clinical variability in disease severity. By applying techniques of mutational analysis and direct sequencing of PCR products it is now potentially possible to determine the pathogenic gene defect in entire haemophilia B populations. We report here characterization of the factor IX gene defect in all the haemophilia B patients in New Zealand as part of a nationwide approach towards providing efficient and cost-effective haemophilia B genetic counselling services for these families. Twenty-six different mutations were identified in 32 unrelated haemophilia B families. Three defects at nucleotide positions +8,6659 and 17696 are novel mutations which have not been reported by other laboratories. A PCR-based diagnostic screening test for direct mutational analysis could be performed in most cases; 17 of the 26 mutations altered a restriction enzyme recognition sequence and, with the exception of the total gene deletion, base changes not affecting a restriction enzyme site could be detected by allele-specific PCR.

Comparison of tests for the lupus anticoagulant and antiphospholipid antibodies in systemic lupus erythematosus.

A variety of laboratory assays are used to screen for the presence of the lupus anticoagulant. Six commonly used coagulation tests, and the ELISA assay for antiphospholipid antibody using three different substrate phospholipids, have been evaluated in 110 patients with systemic lupus erythematosus or lupus-like disease. One or more coagulation assays was abnormal in 41% (45/110) of the patients. No individual test detected more than 78% of these abnormalities, indicating that a single phospholipid based coagulation test cannot be used to screen for a possible lupus anticoagulant. A combination of Actin FSL, DTTA and DRVVT detected all the abnormalities. The most sensitive two-test combination was Actin FSL and DRVVT. Approximately half (56%) of the patients with a positive clotting test had an abnormal antiphospholipid antibody assay. A similar proportion (58%) of the aPL positive patients had a prolonged coagulation test. The marked discordance between the coagulation assays and a positive antiphospholipid antibody test further complicates the laboratory definition of this abnormality, at least in patients with systemic lupus erythematosus.