Hepatitis B screening before rituximab therapy: a multicentre South Australian study of adherence.

BACKGROUND: International guidelines recommend screening for hepatitis B virus (HBV) infection prior to administration of rituximab, due to high risk of HBV reactivation in at-risk patients. AIMS: To determine: (i) adherence to the South Australian (SA) protocol for HBV screening; (ii) HBV prevalence in patients receiving rituximab; and (iii) outcomes of patients at risk of HBV reactivation. METHODS: All patients commenced on rituximab at the six major SA public hospitals during a 12-month period were included in the study. Adherence was assessed by documentation of both hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) prior to initiation of rituximab. Patients were observed for a minimum of 6 months following rituximab initiation. RESULTS: Four hundred and thirty eight patients were included in the study. The main indication for rituximab therapy was haematological malignancy (76.0%). Two hundred and nine (47.7%) failed to receive appropriate HBV screening, 86 (19.6%) had neither HBsAg nor HBcAb performed, and 119 (27.2%) had only HBsAg performed. The identified prevalence of at-risk cases (either HBsAg- or HBcAb-positive) within the study population was 4.6% (20/438 cases). One case of HBV reactivation was identified, but none led to acute liver failure, transplantation or death. CONCLUSIONS: Poor adherence to HBV screening protocols suggests the need for targeted clinician education and system redesign. While the rate of reactivation was low, the prevalence of at-risk patients in this population was high and justifies further initiatives to increase adherence rates to HBV screening pre-rituximab.

Heart failure following blood cancer therapy in pediatric and adult populations.

AIM: The link between chemotherapy treatment and cardiotoxicity is well established, particularly for adults with blood cancers. However, it is less clear for children. This analysis aimed to compare the trajectory and mortality of children and adults who received chemotherapy for blood cancers and were subsequently hospitalized for heart failure. METHODS: Linked data from the Queensland Cancer Registry, Death Registry and Hospital Administration records for initial chemotherapy and later heart failure were reviewed (1996-2009). Of all identified blood cancer patients (N = 23 434), 8339 received chemotherapy, including 817 children (aged ≤18 years at time of cancer diagnosis) and 7522 adults. Time-varying Cox proportional hazards regression models were used to compare the characteristics and survival between the two groups. RESULTS: Of those who were subsequently hospitalized for heart failure, 70% of children and 46% of adults had the index admission within 12 months of their cancer diagnosis. Of these, 53% of the pediatric heart failure population and 71% of the adult heart failure population died within the study period. Following adjustment for age, sex and chemotherapy admissions, children with heart failure had an increased mortality risk compared to their non-heart failure counterparts, a difference which was much greater than that between the adult groups. CONCLUSION: The impact of heart failure on children previously treated for blood cancer is more severe than for adults, with earlier morbidity and greater mortality. Improved strategies are needed for the prevention and management of cardiotoxicity in this population.

Twelve years of experience of acquired hemophilia A: trials and tribulations in South Australia.

Acquired hemophilia A (AH) is a rare and serious acquired bleeding disorder where prompt and correct diagnosis is crucial, and immune suppression is often required for factor VIII (FVIII) autoantibody eradication. The acquired FVIII deficiency usually manifests as bruises and bleeding, and treatment such as FVIII has limited efficacy because of the neutralizing FVIII inhibitor. Expensive bypassing agents such as recombinant activated factor VII (rFVIIa) may be required to treat clinically significant bleeding. This report summarizes the experience related to AH from a large Australian hemophilia center based in South Australia. We identified 25 patients retrospectively over 12 years (1997 to 2008) and reviewed diagnostic features, treatment for bleeds and to eradicate the autoantibody, treatment response, and survival outcomes. The incidence in South Australia was 1.20 cases per million/year with a median age of 78 years with an approximately equivalent sex ratio (12 males versus 13 females); median FVIII and inhibitor titer were 2.5 IU/dL and 11.0 BU/mL, respectively. Twenty-four patients were evaluated further. Thirteen patients (54%) required hemostatic agents, and rFVIIa was used in seven for major bleeds, of which four were limb or life threatening. Eighteen patients were treated by hematologists with immune suppression, and combination steroid and azathioprine was used most commonly to eradicate autoantibody; 15 of these 18 achieved remission (i.e., 83% response rate). Two patients had persistent low-titer inhibitor when treatments were withdrawn, and one died of a fatal bleed shortly after starting treatment. One had spontaneous remission. Five patients (33%) relapsed, three in less than 6 months after starting treatment; all were retreated successfully. Rituximab was used in six patients for high-titer inhibitor, second relapse, two life-threatening bleeds, underlying lymphoma, and steroid intolerance, respectively. Overall mortality was 25% ( N = 6), five of whom were not treated. Advanced age and lack of treatment were predictive of poor survival outcomes. The very elderly (>75 years of age) may warrant a different treatment modality such as rituximab, which is potentially more tolerable and efficacious.

Accuracy and clinical usefulness of the CoaguChek S and XS Point of Care devices when starting warfarin in a hospital outreach setting.

OBJECTIVE: To assess clinical usefulness of CoaguChek S and XS monitors to measure International Normalised Ratio (INR) when starting warfarin in community patients. METHODS: INR in consecutive patients starting warfarin plus enoxaparin was measured in the laboratory and on capillary blood at home using CoaguChek S or XS point of care (POC) devices. INR was measured daily until >2.0 for 2 consecutive readings. Linear regression and Bland Altman plots were derived to compare POC with laboratory INR. Percentages of POC measurements within 0.5 and 0.8 units of laboratory INR <2.0, 2.0-3.5 and >3.5 were calculated. Clinical utility was assessed using previously reported criteria. RESULTS: 200 CoaguChek S and 337 CoaguChek XS results were obtained from 57 and 98 patients respectively and paired with laboratory values. Correlation was acceptable between CoaguChek S and laboratory INRs (r(2)=0.7732), and excellent between CoaguChek XS and laboratory INRs (r(2)=0.9514). Bland-Altman plots showed an increasing difference between laboratory INR above 3.0 for CoaguChek S INRs but no systematic bias with increasing CoaguChek XS INRs. 83.5% of CoaguChek S and 93.5% of CoaguChek XS INRs were within 0.5 units of laboratory INR. 90% of CoaguChek S and 99.4% of the CoaguChek XS INRs were within 0.8 units of laboratory INR. Clinical agreement occurred in 89% and 99.7% of cases by expanded criteria and 82% and 99.4% of cases by narrow criteria when using CoaguChek S and CoaguChek XS respectively. CONCLUSIONS: The CoaguChek XS is suitable for outpatient INR monitoring when starting warfarin.

Emerging technologies in hemostasis diagnostics: a report from the Australasian Society of Thrombosis and Haemostasis Emerging Technologies Group.

Technology in hemostasis laboratories has evolved enormously during the last 30 years. Although many scientists and clinicians will remember the traditional tilt-tube techniques to screen for coagulation abnormalities and to monitor anticoagulant therapy, the hemostasis laboratory today uses a variety of modern technologies. These include flow cytometry, chromogenic assays, molecular typing (e.g., polymerase chain reaction), immunologic assays (e.g., enzyme-linked immunosorbent assays), functional assays of specific coagulation proteins, and platelet function analyzers. Although these advances in technology have resulted in greater capability, productivity, sensitivity, specificity, and ultimately, improvement in the clinical care of patients, controversies and limitations remain. This article highlights new and emerging technologies in hemostasis and discusses whether they have improved or are likely to improve laboratory diagnostics by specifically addressing the following: (1) Can new technologies help predict likelihood of thrombosis recurrence? (2) Has an understanding of the role of A Disintegrin-like And Metalloprotease with Thrombo Spondin type 1 motifs (ADAMTS13) in microangiopathy resulted in improved diagnostic methods for this disorder? (3) Does thrombelastography allow better definition of bleeding risk than conventional hemostasis assays, especially in settings of acute hemostatic pathology?

Heparin pentasaccharide.

Fondaparinux (a synthetic heparin analogue) (Sanofi-Synthelabo; Paris, France and Organon Research; Oss, The Netherlands) is the subject of intense recent clinical evaluation for the prevention and treatment of venous and arterial thromboembolism. The drug replicates the sulphated antithrombin-binding pentasaccharide sequence in heparin and induces potent and specific antithrombin-mediated anti-Xa activity with excellent bioavailability and a long circulating half-life of 18 hours that makes it ideal for once-daily subcutaneous dosing. Its very short chain length ensures this heparin pentasaccharide (PS) is devoid of anti-factor IIa activity. No need for laboratory monitoring is anticipated. Fondaparinux does not cross-react ex vivo with the anti-platelet antibodies responsible for heparin-induced thrombocytopenia. Fondaparinux was evaluated in four large, randomized, placebo-controlled, double-blind phase III trials of deep vein thrombosis prevention after major joint surgery where the PS given after surgery was compared with a low molecular weight heparin (LMWH). LMWH was started before surgery in two comparisons and soon after surgery in the others. The trials shared the same blindly adjudicated efficacy and safety endpoints: efficacy was measured by recording subclinical deep vein thrombosis detected by screening with bilateral venography, plus clinically suspected and confirmed symptomatic thrombosis and embolism; safety was indicated by the rate of major bleeding. Bleeding was considered major if it caused death or reoperation, affected an internal organ, or was overt and associated with a bleeding index of 2 or more. By comparison with LMWH, 2.5 mg/d of the PS beginning 4 to 8 hours after wound closure reduced venous thromboembolism rates by 56% and 26% after elective hip replacement, 63% after knee replacement, and 62% after hip fracture surgery. In three studies and overall, the effect was statistically very significant and included similarly reduced rates of proximal deep vein thrombosis. In absolute terms, the DVT rates with PS are the lowest yet seen after major joint surgery. Trends toward more major bleeding with PS in three studies were statistically significant in one trial. PS did not increase risks from reoperation, internal bleeding, or death because of bleeding, because between-group differences were caused entirely by an excess of patients with a raised bleeding index. Post hoc analysis suggests this excess can be explained by too-early postoperative drug administration and may be avoided without loss of efficacy by giving the first PS injection 6 to 8 hours after surgery. Results of phase III treatment trials for DVT/PE will soon be available, but studies in coronary artery disease are less advanced.