Steve Kitchen

The rare coagulation disorders – review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation

Summary.u2002 The rare coagulation disorders are heritable abnormalities of haemostasis that may present significant difficulties in diagnosis and management. This review summarizes the current literature for disorders of fibrinogen, and deficiencies of prothrombin, factor V, FVu2003+u2003VIII, FVII, FX, the combined vitamin K‐dependent factors, FXI and FXIII. Based on both collective clinical experience and the literature, guidelines for management of bleeding complications are suggested with specific advice for surgery, spontaneous bleeding, management of pregnancy and the neonate. We have chosen to include a section on Ehlers‐Danlos Syndrome because haematologists may be consulted about bleeding manifestations in such patients.

Guidelines on oral anticoagulation with warfarin - fourth edition: Guideline

The writing group was selected to be representative of UK based experts. This guidance is an update of the previous guideline written in 2005 and published in 2006 (Baglin et al, 2006). The guidance is updated with reference to relevant publications since 2005. Publications known to the writing group were supplemented with additional papers identified by searching PubMed for publications in the last 5 years using the key word warfarin and limits clinical trial, randomized control trial, meta-analysis, humans, core clinical journals, and 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 BCSH (British Committee for Standards in Haematology), the British Cardiovascular Society and the British Society for Haematology 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_RECOMMENDATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the indications for and management of patients on warfarin. This guideline replaces the previous BCSH guidelines on oral anticoagulants (Baglin & Rose, 1998; Baglin et al, 2006).

Haemolysis: an overview of the leading cause of unsuitable specimens in clinical laboratories.

Abstract Prevention of medical errors is a major goal of healthcare, though healthcare workers themselves have not yet fully accepted or implemented reliable models of system error, and neither has the public. While there is widespread perception that most medical errors arise from an inappropriate or delayed clinical management, the issue of laboratory errors is receiving a great deal of attention due to their impact on the quality and efficiency of laboratory performances and patient safety. Haemolytic specimens are a frequent occurrence in clinical laboratories, and prevalence can be as high as 3.3% of all of the routine samples, accounting for up to 40%–70% of all unsuitable specimens identified, nearly five times higher than other causes, such as insufficient, incorrect and clotted samples. This article focuses on this challenging issue, providing an overview on prevalence and leading causes of in vivo and in vitro haemolysis, and tentative guidelines on identification and management of haemolytic samples in clinical laboratories. This strategy includes continuous education of healthcare personnel, systematic detection/quantification of haemolysis in any sample, immediate clinicians warning on the probability of in vivo haemolysis, registration of non-conformity, completing of tests unaffected by haemolysis and request of a second specimen for those potentially affected. Clin Chem Lab Med 2008;46:764–72.

Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or rivaroxaban: Guidance from the British Committee for Standards in Haematology

Oral direct inhibitors of thrombin and activated factor X (factor Xa) are now approved as anticoagulant drugs. The first two drugs to complete phase III clinical trials are dabigatran etexilate and rivaroxaban, which are given at fixed dose and do not require monitoring. In most circumstances both have predictable bioavailability, pharmacokinetic and pharmacodynamic effects, however, there will be clinical circumstances when urgent assessment of the anticoagulant effect of these drugs will be required. The effects of dabigatran and rivaroxaban on laboratory tests have been determined in vitro by spiking normal samples with a known concentration of active compound or ex vivo using plasma samples from volunteers and patients. To date there are few data on the sensitivity of different reagents and so only general guidance as to the effect and interpretation of a test result can be given at present. Laboratories should be aware of the sensitivity of their own assays to each drug, which can be achieved using commercially available dabigatran and rivaroxaban calibrants. Dabigatran etexilate is an oral prodrug that is hydrolysed in the liver to the direct thrombin inhibitor dabigatran. Doses recommended for clinical use are 150 mg od, 220 mg od, 110 mg bd and 150 mg bd. Peak plasma levels are reached 2 to 3 h after ingestion. Dabigatran is 80% renally excreted with a half-life of approximately 13 h with a glomerular filtration rate (GFR) of >80 ml/min, and 18 h with a GFR of 30–50 ml/min. There is a dose-dependent effect of dabigatran on laboratory clotting tests (Wienen et al, 2007; van Ryn et al, 2010; Freyburger et al, 2011; Lindahl et al, 2011). Rivaroxaban is an oral direct inhibitor of factor Xa. Doses recommended for clinical use are 10 mg od and 20 mg od (15 mg bd for first 3 weeks of treatment of DVT). Peak plasma levels are reached 2 to 3 h after ingestion. Rivaroxaban is 33% renally excreted and has a half-life of 9 h in patients with normal renal function. There is a dose-dependent effect of rivaroxaban on laboratory clotting tests (Samama et al, 2010; Freyburger et al, 2011; Hillarp et al, 2011). For both drugs, peak plasma concentrations are in the range of 100 to 400 ng/ml. Trough concentrations are in the range of 20 to 150 ng/ml. Clinicians require knowledge as to how routine coagulation tests are affected because many patients having a ‘coagulation screen’ will be taking these drugs. They also need to know if and how the degree of anticoagulation can be assessed using routine coagulation tests. Urgent assessment of the degree of anticoagulation may be required

Preanalytical quality improvement: in quality we trust

Abstract Total quality in laboratory medicine should be defined as the guarantee that each activity throughout the total testing process is correctly performed, providing valuable medical decision-making and effective patient care. In the past decades, a 10-fold reduction in the analytical error rate has been achieved thanks to improvements in both reliability and standardization of analytical techniques, reagents, and instrumentation. Notable advances in information technology, quality control and quality assurance methods have also assured a valuable contribution for reducing diagnostic errors. Nevertheless, several lines of evidence still suggest that most errors in laboratory diagnostics fall outside the analytical phase, and the pre- and postanalytical steps have been found to be much more vulnerable. This collective paper, which is the logical continuum of the former already published in this journal 2 years ago, provides additional contribution to risk management in the preanalytical phase and is a synopsis of the lectures of the 2nd European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)-Becton Dickinson (BD) European Conference on Preanalytical Phase meeting entitled “Preanalytical quality improvement: in quality we trust” (Zagreb, Croatia, 1–2 March 2013). The leading topics that will be discussed include quality indicators for preanalytical phase, phlebotomy practices for collection of blood gas analysis and pediatric samples, lipemia and blood collection tube interferences, preanalytical requirements of urinalysis, molecular biology hemostasis and platelet testing, as well as indications on best practices for safe blood collection. Auditing of the preanalytical phase by ISO assessors and external quality assessment for preanalytical phase are also discussed.

Point-of-care testing in haemostasis.

Point‐of‐care testing (POCT) in haematology has seen a significant increase in both the spectrum of tests available and the number of tests performed annually. POCT is frequently undertaken with the belief that this will reduce the turnaround time for results and so improve patient care. The most obvious example of POCT in haemostasis is the out‐of‐hospital monitoring of the International Normalized Ratio in patients receiving a vitamin K antagonist, such as warfarin. Other areas include the use of the Activated Clotting Time to monitor anticoagulation for patients on cardio‐pulmonary bypass, platelet function testing to identify patients with apparent aspirin or clopidogrel resistance and thrombelastography to guide blood product replacement during cardiac and hepatic surgery. In contrast to laboratory testing, POCT is frequently undertaken by untrained or semi‐trained individuals and in many cases is not subject to the same strict quality control programmes that exist in the central laboratory. Although external quality assessment programmes do exist for some POCT assays these are still relatively few. The use of POCT in haematology, particularly in the field of haemostasis, is likely to expand and it is important that systems are in place to ensure that the generated results are accurate and precise.

Causes, consequences, detection, and prevention of identification errors in laboratory diagnostics.

Abstract Laboratory diagnostics, a pivotal part of clinical decision making, is no safer than other areas of healthcare, with most errors occurring in the manually intensive preanalytical process. Patient misidentification errors are potentially associated with the worst clinical outcome due to the potential for misdiagnosis and inappropriate therapy. While it is misleadingly assumed that identification errors occur at a low frequency in clinical laboratories, misidentification of general laboratory specimens is around 1% and can produce serious harm to patients, when not promptly detected. This article focuses on this challenging issue, providing an overview on the prevalence and leading causes of identification errors, analyzing the potential adverse consequences, and providing tentative guidelines for detection and prevention based on direct-positive identification, the use of information technology for data entry, automated systems for patient identification and specimen labeling, two or more identifiers during sample collection and delta check technology to identify significant variance of results from historical values. Once misidentification is detected, rejection and recollection is the most suitable approach to manage the specimen. Clin Chem Lab Med 2009;47:143–53.

Measurement of non-coumarin anticoagulants and their effects on tests of Haemostasis: Guidance from the British Committee for Standards in Haematology.

Steve Kitchen, Elaine Gray, Ian Mackie, Trevor Baglin and Mike Makris on behalf of the BCSH committee Sheffield Haemophilia and Thrombosis Centre, Sheffield Teaching Hospitals NHS Trust, Sheffield, Haemostasis section, Biotherapeutics Group, National Institute for Biological Standards and Control, Potters Bar, Haemostasis Research Unit, Department of Haematology, University College London, London, Department of Haematology, Addenbrooke’s Hospital, Cambridge, and Department of Cardiovascular Science, University of Sheffield, Sheffield, UK

Multicenter evaluation of the hemolysis index in automated clinical chemistry systems

Abstract Background: In vitro hemolysis, the prevailing cause of preanalytical error in routine laboratory diagnostics, might influence the reliability of several tests, affect the quality of the total testing process and jeopardize patient safety. Although laboratory instrumentation is now routinely equipped with systems capable of automatically testing and eventually correcting for hemolysis interference, to our knowledge there are no reports that have compared the efficiency of different analytical platforms for identifying and classifying specimens with hemolysis. Methods: Serum from a healthy volunteer was spiked with varying amounts of hemolyzed blood from the same volunteer, providing a serum free hemoglobin concentration ranging from 0.0 g/L to 2.0 g/L as measured by the reference cyanmethemoglobin assay. The spiked serum samples were shipped to seven separate laboratories and the hemolysis index (HI) was tested in triplicate on the following analytical platforms: Roche Modular System P (n=4) and Integra 400 Plus (n=1), Siemens Dimension RxL (n=3), ADVIA 2400 (n=1) and ADVIA 1800 (n=1), Olympus AU 680 (n=1) and Coulter DXC 800 (n=1). Results: Satisfactory agreement of HI results was observed among the various analytical platforms, despite a trend toward overestimation by the ADVIA 2400 and 1800. After normalizing results according to the instrument-specific alert value, discrepancies were considerably reduced. All instruments except for the Dimension RxL gave values normalized to the instrument-specific alert value, <1.0 for the sample with 0.048 g/L free hemoglobin, and >1.0 for the sample with 0.075 g/L free hemoglobin. The results of the four Modular System P tests were also highly reproducible among the different facilities. When evaluating instruments that provided quantitative HI results, the mean intra-assay coefficient of variation (CV) calculated for the triplicate determinations was always between 0.1% and 2.7%. Conclusions: The results of this multicenter evaluation confirm that efficiency of different analytical platforms to correctly identify and classify unsuitable samples is satisfactory. However, more effort should be placed on the standardization of reporting HI. All the instruments that we tested provide either quantitative or qualitative results that are essentially comparable, but which should always be compared with the instrument-specific alert values to harmonize their efficiency. Clin Chem Lab Med 2009;47:934–9.

Dabigatran Effects on the International Normalized Ratio, Activated Partial Thromboplastin Time, Thrombin Time, and Fibrinogen: A Multicenter, In Vitro Study:

Background: Patients receiving the direct thrombin inhibitor dabigatran may have selected anticoagulation assays performed as part of routine care. The effect of dabigatran on the international normalized ratio (INR), activated partial thromboplastin time (aPTT), thrombin time (TT), and fibrinogen requires clarification. Objective: To describe the effect of dabigatran on selected assays in North America and the United Kingdom. Methods: Pooled normal plasma enriched with dabigatran at concentrations of 25, 50, 75, 100, 125, 150, 200, 300, 400, and 500 ng/mL were sent blinded to 19 centers in the US, the UK, and Canada to assess the effect of dabigatran on routine coagulation screening tests, the INR, aPTT, TT, and fibrinogen. Results: Data were returned from 16 centers. For effects on INR, Neoplastine CI Plus and Simplastin HTF were the most sensitive and Thromborel S the least sensitive to increasing dabigatran concentrations. For the aPTT, all reagents demonstrated decreasing sensitivity to increasing dabigatran concentrations. Measured fibrinogen either demonstrated no change or factitious decrease with increasing dabigatran concentrations. Commercial TT methods were very sensitive to low concentrations of dabigatran, with 9 of 10 reporting sites exceeding test limits at dabigatran concentrations of 100 ng/mL. Conclusions: The INR, aPTT, and TT rise as dabigatran concentrations increase. Both the INR and aPTT increase in a linear pattern with marginal slopes, creating challenges in using these assays as reliable means for assessing the amount of dabigatran present. The commercial TT assay is very sensitive at low concentrations of dabigatran. Fibrinogen test results may be either unaffected or lower in the presence of dabigatran.