Hannah Cohen

Guidelines on the investigation and management of antiphospholipid syndrome

This guidance updates and replaces the previous guideline on the investigation and management of antiphospholipid syndrome (APS) published in 2000 (Greaves et al, 2000), though where there have not been changes we refer back to them when appropriate. The guidance is updated with reference to relevant publications since 2000. Publications known to the writing group were supplemented with additional papers identified by searching PubMed for publications in the last 11 years using the key words: lupus anticoagulant, anticardiolipin, antiphospholipid, b2–glycoprotein I, antiprothrombin and limits (clinical trial, randomized control trial, meta-analysis, humans, core clinical journals, English language). The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the Royal College of Obstetricians and Gynaecologists (RCOG), and the British Committee for Standards in Haematology (BCSH) Committee and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMEN DATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with antiphospholipid syndrome though individual patient circumstances may dictate an alternative approach.

Serious hazards of transfusion (SHOT) initiative: analysis of the first two annual reports

Abstract Objective: To receive and collate reports of death or major complications of transfusion of blood or components. Design: Haematologists were invited confidentially to report deaths and major complications after blood transfusion during October 1996 to September 1998. Setting: Hospitals in United Kingdom and Ireland. Subjects: Patients who died or experienced serious complications, as defined below, associated with transfusion of red cells, platelets, fresh frozen plasma, or cryoprecipitate. Main outcome measures: Death, “wrong” blood transfused to patient, acute and delayed transfusion reactions, transfusion related acute lung injury, transfusion associated graft versus host disease, post-transfusion purpura, and infection transmitted by transfusion. Circumstances relating to these cases and relative frequency of complications. Results: Over 24 months, 366 cases were reported, of which 191 (52%) were “wrong blood to patient” episodes. Analysis of these revealed multiple errors of identification, often beginning when blood was collected from the blood bank. There were 22 deaths from all causes, including three from ABO incompatibility. There were 12 infections: four bacterial (one fatal), seven viral, and one fatal case of malaria. During the second 12 months, 164/424 hospitals (39%) submitted a “nil to report” return. Conclusions: Transfusion is now extremely safe, but vigilance is needed to ensure correct identification of blood and patient. Staff education should include awareness of ABO incompatibility and bacterial contamination as causes of life threatening reactions to blood. Key messages Blood transfusion, while extremely safe, has several potentially fatal hazards All staff handling blood should be aware of the importance of correct identity of sample, patient, and blood bag at all stages Resources should be directed to evaluation of methods for improving identification of patients Acute fever or collapse during or after transfusion may be due to ABO incompatibility or bacterial contamination Microbiological complications of transfusion accounted for a minor component of all reports

Ten years of hemovigilance reports of transfusion‐related acute lung injury in the United Kingdom and the impact of preferential use of male donor plasma

BACKGROUND AND METHODS: From 1996 through 2006, 195 cases were reported as transfusion‐related acute lung injury (TRALI) to the Serious Hazards of Transfusion scheme and from 1999 onward classified by probability, using clinical features and HLA and/or HNA typing. From late 2003, the National Blood Service provided 80 to 90 percent of fresh‐frozen plasma (FFP) and plasma for platelet (PLT) pools from male donors.

A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura.

The safety and efficacy of weekly rituximab 375 mg/m(2) (×4), given within 3 days of acute TTP admission, with standard therapy (PEX and steroids) was evaluated. Clinical outcomes were compared to historical controls (n = 40) who had not received rituximab. Within the trial group, 15 of 40 required ICU admission and 15% of all cases with the highest troponin T levels on admission were ventilated. Before the second rituximab infusion, 68% of cases had a platelet count > 50 × 10(9)/L and 38% > 150 × 10(9)/L. Fewer PEX were required in whites compared to nonwhite in the rituximab group (mean 14 vs 21, P = .0095). Inpatient stay was reduced by 7 days in the non-ICU trial cases compared to historical controls (P = .04), especially in whites, with a mean reduction of 7 days (P = .05). Ten percent of trial cases relapsed, median, 27 months (17-31 months), compared to 57% in historical controls, median 18 months (3-60 months; P = .0011). There were no excess infections or serious adverse events with rituximab. In conclusion, rituximab appears a safe and effective therapy. Inpatient stay and relapse are significantly reduced in the rituximab cohort. Rituximab should be considered in conjunction with standard therapy on acute presentation of TTP. This study was registered at www.clinicaltrials.gov as NCT009-3713.

Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13

Thrombotic thrombocytopenic purpura (TTP) is a life‐threatening disorder and plasma exchange (PEX) remains the primary treatment modality. Twenty‐five patients with acute refractory/relapsing idiopathic TTP received rituximab in conjunction with PEX because of progressive clinical disease or deterioration in laboratory parameters, despite intensive standard therapy. In relapsing TTP, rituximab was started if antibody to ADAMTS‐13 (a disintegrin and metalloproteinase with thrombospondin motif‐13) was demonstrated during previous episodes. All 25 patients attained complete clinical and laboratory remission in a median of 11 d after initiating rituximab. In 21 cases, ADAMTS‐13 activity was within the normal range following rituximab. Inhibitors were detected in 24/25 patients by mixing studies and/or immunoglobulin G (IgG) antibodies to ADAMTS‐13 pre‐rituximab. There was no evidence of inhibitors and/or IgG activity <10% in 23/25 patients following rituximab. In acute refractory cases, the median number of PEX pre‐rituximab and following the first rituximab infusion was 13 and 9, respectively. There have been no infectious complications, despite low CD 19 levels and no relapses. In patients with acute refractory/relapsing idiopathic TTP, rituximab appears to be a safe, effective, targeted therapy with a significant reduction in the requirement for PEX.

14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends.

Antiphospholipid Syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity occurring in patients with persistent antiphospholipid antibodies (aPL). The primary objective of the APS Treatment Trends Task Force, created as part of the 14th International Congress on aPL, was to systematically review the potential future treatment strategies for aPL-positive patients. The task force chose as future clinical research directions: a) determining the necessity for controlled clinical trials in venous thromboembolism with the new oral direct thrombin or anti-factor Xa inhibitors pending the results of the ongoing rivaroxaban in APS (RAPS) trial, and designing controlled clinical trials in other forms of thrombotic APS; b) systematically analyzing the literature as well as aPL/APS registries, and creating specific registries for non-warfarin/heparin anticoagulants; c) increasing recruitment for an ongoing primary thrombosis prevention trial, and designing secondary thrombosis and pregnancy morbidity prevention trials with hydroxychloroquine; d) determining surrogate markers to select patients for statin trials; e) designing controlled studies with rituximab and other anti-B-cell agents; f) designing mechanistic and clinical studies with eculizumab and other complement inhibitors; and g) chemically modifying peptide therapy to improve the half-life and minimize immunogenicity. The report also includes recommendations for clinicians who consider using these agents in difficult-to-manage aPL-positive patients.

Serious Hazards of Transfusion (SHOT) haemovigilance and progress is improving transfusion safety.

The Serious Hazards of Transfusion (SHOT) UK confidential haemovigilance reporting scheme began in 1996. Over the 16 years of reporting, the evidence gathered has prompted changes in transfusion practice from the selection and management of donors to changes in hospital practice, particularly better education and training. However, half or more reports relate to errors in the transfusion process despite the introduction of several measures to improve practice. Transfusion in the UK is very safe: 2·9 million components were issued in 2012, and very few deaths are related to transfusion. The risk of death from transfusion as estimated from SHOT data in 2012 is 1 in 322 580 components issued and for major morbidity, 1 in 21 413 components issued; the risk of transfusion‐transmitted infection is much lower. Acute transfusion reactions and transfusion‐associated circulatory overload carry the highest risk for morbidity and death. The high rate of participation in SHOT by National Health Service organizations, 99·5%, is encouraging. Despite the very useful information gained about transfusion reactions, the main risks remain human factors. The recommendations on reduction of errors through a ‘back to basics’ approach from the first annual SHOT report remain absolutely relevant today.

Venous thromboembolism associated with the management of acute thrombotic thrombocytopenic purpura

Summary. Venous thromboembolism (VTE) is not a feature of thrombotic thrombocytopenic purpura (TTP), but there has been a recent report of VTE in association with plasma exchange (PEX) treatment for TTP using the solvent detergent (SD) plasma, PLAS+®SD. We reviewed the occurrence of VTE in 68 consecutive patients with TTP (25 men, 43 women). Eight documented VTE events [six deep venous thromboses (DVTs), three pulmonary emboli] were identified in seven patients (all female) during PEX therapy. All six DVTs were associated with central lines at the site of thrombosis. Other known precipitating factors included pregnancy, immobility, obesity and factor V Leiden heterozygosity. VTE occurred at a mean of 53 d following the first PEX. The European SD plasma, Octaplas® was the last plasma to be used in PEX prior to the VTE in 7/8 events. This is the first report of VTE following Octaplas® infusion. VTE is a multifactorial disease and, although several known precipitating factors were present in all patients in this study, the use of large volumes of SD plasma in PEX may be an additional risk factor. We recommend prevention of VTE with graduated elastic compression stockings (class I) at diagnosis and prophylactic low‐molecular‐weight heparin once the platelet count rises above 50 × 109/l.

Patient self-testing is a reliable and acceptable alternative to laboratory INR monitoring

An ageing population and the continuing expansion of clinical indications for coumadin therapy have increased pressure on hospital anticoagulant clinics. One solution is patient self‐testing (PST) of the international normalized ratio (INR) using capillary blood samples on point‐of‐care coagulation monitors at home. We conducted a prospective study to determine whether patients can achieve accurate INR values through PST, using the CoaguChek S (Roche Diagnostics, Lewes, UK). The main outcome measurements were: comparability of INR values obtained by PST and the hospital laboratory, patient acceptability as assessed by a questionnaire and anticoagulant control. Eighty‐four patients [53 men, 31 women; median age 59 years (range 26–83)], receiving long‐term oral anticoagulation (warfarin), were recruited from our Anticoagulation Clinic. Patients were randomized to weekly self‐testing or continuing 4‐weekly hospital laboratory monitoring of INR. Comparison of INRs (n = 234) showed no significant differences between the CoaguChek (median INR 3·02) and laboratory testing (median INR 3·07). There was excellent correlation between the two methods (r = 0·95), with 85% of CoaguChek results within 0·5 INR units of the laboratory method. On four occasions, differences of >1 unit INR were obtained, but in each case the patients anticoagulation was unstable (INR >4·5 by both methods) and the differences in INR would not have altered patient management. 87% of patients found self‐testing straightforward, 87% were confident in the result they obtained and 77% preferred self‐testing. We conclude that PST is a reliable alternative to hospital clinic attendance and is acceptable to the majority of suitably trained patients.

Adverse outcomes of blood transfusion in children: analysis of UK reports to the serious hazards of transfusion scheme 1996–2005

Between 1996 and 2005 the Serious Hazards of Transfusion (SHOT) scheme analysed 3239 reports of adverse reactions and events associated with transfusion of labile blood components in the UK. 321 reports (10%) related to transfusion of children under 18 years and 147/3239 (4·5%) to infants less than 12 months of age. There were 264 cases in children of ‘incorrect blood component transfused’, resulting from errors at all stages in the transfusion chain; 26/264 suffered actual or potential morbidity. Thirty acute transfusion reactions, three delayed transfusion reactions, 20 cases (three fatal) of transfusion‐related acute lung injury, two cases (both fatal) of transfusion‐associated graft‐versus‐host disease and two transfusion transmitted infections were reported. A population‐based epidemiological study of transfused patients in 2004 showed that 4·2% of red cells are transfused to patients less than 18 years and 1·7% to infants less than 12 months. Interpretation of SHOT data against this context enabled the estimation of the incidence of an adverse outcome to be 18:100 000 red cells issued for children less than 18 years and 37:100 000 for infants less than 12 months, compared to 13:100 000 for adults. Adherence to relevant guidelines, knowledge of specialist transfusion needs of children and good communication are essential if this risk is to be reduced.