Hemostasis Laboratory Research Articles

Mis-identification of factor inhibitors by diagnostic haemostasis laboratories: recognition of pitfalls and elucidation of strategies. A follow up to a large multicentre evaluation

We previously reported the ability of diagnostic haemostasis facilities to identify coagulation factor abnormalities and inhibitors, through a large multi-centre study conducted on behalf of the Royal College of Pathologists of Australasia (RCPA) Quality Assurance Program (QAP). In the current report, additional data evaluation aims to (1) help identify the reasons behind the failures in inhibitor identification, (2) highlight the pitfalls in inhibitor testing, and (3) help elucidate some strategies for overcoming these problems and to assist in better identification and characterisation of inhibitors. Forty-two laboratories blind tested a set of eight samples for the presence or absence of inhibitors. These included true factor inhibitors (FVIII and FV), and other samples that reflected potential pre-analytical variables (e.g., heparin contamination, serum, EDTA plasma, aged plasma) that might arise and complicate inhibitor detection or lead to false inhibitor identification. There was a wide scatter of inhibitor results, with false positive and false negative inhibitor identification, and mis-identification of inhibitors (e.g., FVIII inhibitor identified where FV inhibitor present). Further analysis of the pattern of reported laboratory results, including routine coagulation testing and factor profiles, allowed some additional interpretative power to provide strategies that will assist laboratories to improve the accuracy of inhibitor identification in the future. There are currently occasional lapses in factor inhibitor identification, which this report will hopefully help address.

Utility of the PFA-100 as a screening test of platelet function: an audit of haemostasis laboratories in Australia and New Zealand

The PFA-100 is a relatively new laboratory instrument, first described in 1995. There have since been numerous studies assessing its utility as a screening tool for platelet dysfunction and/or von Willebrand's disease (VWD). The PFA-100 displays variable sensitivity to different types of platelet disorders, as well as to antiplatelet medication (e.g. aspirin), with similar caveats for monitoring of primary haemostasis-promoting therapies in platelet dysfunction. There is therefore considerable uncertainty regarding its utility within this context, and we have accordingly performed an audit of usage among participants of the Royal College of Pathologists of Australasia Quality Assurance Program. Of 105 laboratories surveyed, 40 responded that they performed platelet function testing, with 26 (65%) further indicating they utilized the PFA-100. We report a wide variety of laboratory usage among these users, including numbers of tests performed [annual median (range) = 270 (15-6000)], sources of requests (clinical sources and localities), testing criteria and follow-up action. Most tests were completed within 4 h of collection, as recommended by the manufacturer, and most tests were performed as a replacement, or as a preliminary screen of platelet function (i.e. classical aggregation). Most abnormal findings, however, were attributed to antiplatelet medication such as aspirin.

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?

Emerging Technologies and Quality Assurance: The United Kingdom National External Quality Assessment Scheme Perspective

The pattern of tests employed and technologies developed within hemostasis laboratories has changed considerably within the last 10 years. These changes have presented challenges to external quality assessment (EQA) providers, including the United Kingdom National External Quality Assessment Scheme (NEQAS). EQA for point-of-care devices used for monitoring oral anticoagulant therapy has focused on provision of suitable material to assess performance of devices designed for capillary blood testing, and on education of a user group not usually trained in laboratory quality control procedures. Development of novel therapeutic agents for hemophilia has presented challenges regarding standardization of assays for monitoring treatment, whereas advances related to laboratory testing and automation have not always been accompanied by improved accuracy and precision. EQA provision has also been shown to be of value in molecular genetic screening tests for thrombophilia, and in highlighting standardization issues related to D-dimer measurement in the exclusion of deep vein thrombosis. The increasing prevalence of screening tests of global hemostasis, such as thrombin generation tests and thromboelastography, presents additional challenges to EQA providers in the attempt to standardize these new and potentially beneficial technologies.

Standardization, Regulation, Quality Assurance and Emerging Technologies in Hemostasis: Issues, Controversies, Benefits, and Limitations

There are many benefits to the overall process of standardization for tests of hemostasis and thrombosis. Nevertheless, it should also be recognized there are several specific problems and limitations to this process, as highlighted in this review. Some of the issues are formidable, but it is hoped that they are not insurmountable. Sometimes, clinical pressures drive diagnostic test processes before they are formally proven to be of clinical value. Such clinical pressures drive diagnostic changes in the hemostasis laboratory, including the incorporation of new and emerging technologies, which in turn drives the need for evolving and effective external quality assurance. Incorporated into the diagnostic or test-performance process are a large number of organizations involved in driving standardization, with the ultimate intention of improving diagnostics, but this process will also have unintended potential for adverse outcomes. Although this review notes many of the benefits to the process, it focuses primarily on those negative factors that are often less obvious but still require attention and process review.

Standardization, Quality Assurance, and Emerging Diagnostic Technologies in Hemostasis

This issue of Seminars in Thrombosis and Hemostasis reviews several aspects of the standardization and quality assurance in laboratory hemostasis as well as noting the emergence of several new diagnostic technologies in the field.

Quality Assurance in Hemostasis: The Perspective from the College of American Pathologists Proficiency Testing Program

External quality assurance (EQA) is an important component of the total quality assurance program of a clinical hemostasis laboratory. The College of American Pathologists (CAP) helps meet this requirement by providing a proficiency testing program that evaluates a broad range of hemostasis methods and analytes. This article reviews the published experience of the CAP proficiency testing program in hemostasis. The purpose is to formulate general conclusions about the benefits of EQA. Between 1963 and 2006, the performance characteristics of a variety of tests have been evaluated, including the prothrombin time, activated partial thromboplastin time, coagulation factor activity assays (e.g., fibrinogen, factor [F] VIII, FIX, FXI), von Willebrand factor assays, unfractionated heparin monitoring, lupus anticoagulant testing, and platelet function. Based on the results of these evaluations, the major benefits of EQA are to (1) enhance patient care and safety through improved laboratory testing; (2) characterize test accuracy and precision across multiple methods; (3) correlate specific method variables with accuracy and precision; (4) identify interfering substances and quantify their effects across multiple methods; (5) identify clinical laboratories that are at risk for poor performance so that their performance can improve; and (6) satisfy accreditation and regulatory requirements.

The Utility of the PFA-100 in the Identification of von Willebrand Disease: A Concise Review

The PFA-100 (platelet function analyser; Dade-Behring, Marburg, Germany) is a relatively new tool for the investigation of primary hemostasis. Recent studies have shown its utility as a screening tool for investigating various platelet disorders and possible von Willebrand disorder (vWD), both in the initial investigation and in subsequent therapeutic monitoring of desmopressin therapy. This article reviews current findings with respect to the identification of vWD, and highlights both the benefits and the limitations of its clinical utility. In brief, sensitivity to vWD types 2A, 2B, 2M, and 3 is > 98%, but overall sensitivity to vWD (types 1, 2A, 2B, 2M, and 3 combined) is ~85 to 90%. Ultimately, the high sensitivity of the PFA-100 to vWD and its simplicity of use provide its greatest strengths. However, because it is a global test system, and also sensitive to low hematocrit, low platelet counts, and platelet dysfunction (both congenital and acquired; e.g., secondary to medication such as aspirin) it must be recognized that the PFA-100 is neither specific for, nor predictive of, any particular disorder (inclusive of vWD). Nevertheless, used appropriately, the PFA-100 can be considered a worthwhile addition to the hemostasis laboratory involved in the diagnosis or therapeutic monitoring of vWD, and a normal PFA-100 result can be used with some confidence to exclude severe vWD.

Recombinant activated factor VIIa in uncontrolled bleeding: a haemostasis laboratory study in non-haemophilia patients

Extensive surgery and massive tissue trauma are often associated with severe bleeding. We present retrospective data on the use of recombinant factor VIIa in haemostatic emergencies in13 non-hemophilia patients with uncontrolled bleeding. Recombinant factor VIIa was administered in doses ranging from 16 mug/kg bodyweight to 60 microg/kg bodyweight. Blood loss during 24 h before and after the infusion was registered, showing that 10 out of 13 patients (77%) had a 70% or greater reduction in transfusion requirement decreasing significantly in mean from 28.1 to 9.9 red blood cell units. Coagulation parameters were studied in blood samples collected 10 min before and 10-15 min after the injection of recombinant factor VIIa. Factors VII:C, II:C, and X:C increased significantly while the activated partial thromboplastin time, platelet numbers, and concentration of fibrinogen and D-dimers were unchanged. The dose of rFVIIa correlated significantly with the rise in factor X:C and inversely with transfusion requirements. Dynamic clot velocity of whole blood was recorded before and after rFVIIa infusion in four patients. Judged from red blood cell usage no improvement in haemostasis was seen in one patient suffering thrombocytopenia and low fibrinogen. This patient died 6 h after recombinant factor VIIa infusion, and three other patients died before 1 month. None of the fatalities appeared to be related to recombinant factor VIIa usage. No thromboembolic complications were seen. In conclusion, 12 out of 13 patients survived the first 24 h after treatment with relatively low doses of recombinant factor VIIa for large-scale bleeding. Recombinant factor VIIa was well tolerated and safe in these non-hemophilia patients. With quite low doses of recombinant factor VIIa (<or= 60 microg/kg), the dose of recombinant factor VIIa correlated positively with efficacy. Activation of factor X appeared to predict haemostatic efficacy.

Platelet function analyzer (PFA)‐100® closure time in the evaluation of platelet disorders and platelet function – a rebuttal

Platelet function analyzer (PFA)‐100® closure time in the evaluation of platelet disorders and platelet function – a rebuttal

Identification of factor inhibitors by diagnostic haemostasis laboratories

We have assessed the proficiency of diagnostic haemostasis facilities to correctly identify coagulation factor abnormalities and inhibitors. Forty-two laboratories participating in the external Quality Assurance Program (QAP) conducted by the RCPA agreed to participate and were each sent a set of eight samples (each 3 x 1 ml) for evaluation. They were asked to blind test these samples for the presence or absence of inhibitors, and where identified, to perform further analysis (including specific inhibitor analysis). In order to make the exercise more challenging, in addition to true factor inhibitors, samples were provided that reflected potential pre-analytical variables that might arise and complicate inhibitor detection or lead to false inhibitor identification. In brief, the sample set comprised a true high level factor (F) V inhibitor, a true moderate level FVIII inhibitor (but sample was defibrinogenated), a true lupus anticoagulant (LA), a normal (but slightly aged) plasma sample, a normal serum sample, a normal EDTA sample, an oral anticoagulant/vitamin K deficiency sample, and a gross heparin ( approximately 10 U/ml) contaminated sample. Sixty-three percent of participants correctly identified the true FV inhibitor as such, although the reported range varied greatly [10 to >250 Bethesda units (BU/ml)] and 46% correctly identified the true FVIII inhibitor, despite the complication of the sample presentation, although the reported range also varied (7 to 64 BU/ml). Some laboratories either failed to identify the inhibitor present, or misidentified the inhibitor type. The LA, the oral anticoagulant/vitamin K deficiency, the normal serum sample, and the normal (aged) sample were also correctly identified by most laboratories, as was the absence of specific factor inhibitors in these samples. However, a small subset of laboratories incorrectly identified the presence of specific factor inhibitors in some of these samples. The heparin sample was also correctly identified by most (68%) laboratories. In contrast, the normal EDTA sample was misidentified as a FV and/or FVIII inhibitor by most (68%) laboratories, and only one laboratory correctly identified this as an EDTA sample. Thus, we conclude that although laboratories are able, in most cases, to identify the presence of true factor inhibitors, there is a large variation in identified inhibitor levels and there are also some significant errors in identification (i.e. false negatives and misidentifications). In addition, there is a significant false positive error rate where some laboratories will identify the presence of specific factor inhibitors where no such inhibitor exists (i.e. false positives).

Comparability of D-Dimer Assays in Clinical Samples

D-dimers (DD) have shown sufficient proof of their efficiency in the last 10 years to play an important role in hemostasis laboratories for excluding thromboembolic events. Numerous reagents are available on the market but their performances differ. This overview takes stock of the methods used to evaluate the performances of DD assays, the results published in the literature, the technical parameters influencing assay performance, the difficulties caused by the lack of harmonization of DD units, and the attempts to tackle this problem. It raises the issue of the potential optimization of their use with regard to better adaptation to multidisciplinary diagnostic strategies and to target patient populations.

Tailoring haemostatic treatment to patient requirements – an update on monitoring haemostatic response using thrombelastography

Currently, there is no single haemostasis laboratory test that has the capacity to accurately illustrate the clinical effects of procoagulant or anticoagulant interventions. Although the time course of thrombin generation in plasma and the endogenous thrombin potential (ETP) may be useful coagulation parameters, clotting involves components other than thrombin (e.g. platelets, fibrinogen). The continuous coagulation profiles of thrombelastography may provide a more accurate reflection of in vivo biology, covering initiation, development and final clot strength during whole blood clot formation. This method has helped to clarify the mechanism of action of whole blood clot formation, demonstrating the differences from clotting in plasma, and the importance of platelets and tissue factor titrations. It has also been used to investigate hypocoagulation (in haemophilia A, rare coagulation disorders, anticoagulant therapy and dilutional coagulopathy), hypercoagulation and the ex vivo testing of haemostatic interventions. Thrombelastography has been shown to reflect the clinical efficacy of activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa) in patients with haemophilia A with inhibitors and in patients with acquired haemophilia. Overall, tailoring laboratory assays to illustrate and correlate with clinical phenotypes is essential for effective coagulation monitoring. Applying an algorithm of preoperative, perioperative and postoperative tests, including thrombelastography, may enable physicians to achieve this.

Laboratory Identification of Familial Thrombophilia: Do the Pitfalls Exceed the Benefits? A Reassessment of ABO-Blood Group, Gender,Age, and other Laboratory Parameters on the Potential Influence on a Diagnosis of Protein C, Protein S, and Antithromb

Laboratory testing for familial thrombophilia defines a large proportion of the modern hemostasis laboratory workload. As part of an ongoing assessment of our activities, we have re-evaluated our laboratory procedures for antithrombin (AT), Protein C (PC), and Protein S (PS), inclusive of normal reference ranges (NRR), the potential influence of ABO-blood group, gender and age, as well as other laboratory parameters, in order to help assess the effectiveness of testing as an aid to clinical diagnosis. We did not observe a significant influence of ABO-blood group on AT, PC, or PS. However, there were gender-related effects for PS (lower in females) and AT (higher in females), but not for PC. There were also age-related effects for AT, PC, and PS. Data is compared with literature findings. We also audited the positive detection rate for PC and/or PS deficiencies. In a 6-month period of testing, we identified that 18.9% of tested samples yielded low or near-low PC and/or PS levels. However, 33.3% of such samples were potentially derived from patients on oral anticoagulant therapy (ie, potential false positives). Additional pre-analytical variables, intra-assay, inter-assay, and inter-laboratory variability also contribute to the possibility of false positive detection. Thus, whilst NRR can be developed for test parameters, the likelihood of a false-positive test result can still be shown to exceed the likelihood of a true positive result, and this casts a shadow over the clinical value of such testing in some cases. In conclusion, laboratory testing for these markers of familial thrombophilia may or may not assist in the clinical diagnosis of this condition and clinical specialists should be made aware of laboratory test limitations, and consult with laboratories prior to making a definitive diagnosis of AT, PC, or PS deficiency.

Lupus anticoagulant testing using plasma spiked with monoclonal antibodies: performance in the UK NEQAS proficiency testing programme

We report here results from a United Kingdom National Quality Assessment Scheme (UK NEQAS) exercise in which both plasma spiked with monoclonal antibodies and plasma from a patient known to have lupus anticoagulant (LA) were distributed to 245 hemostasis laboratories with a request for them to test for possible LA using their routine screening procedure. In general, good agreement was seen in the diagnosis of samples spiked with monoclonal antibodies against beta2-glycoprotein 1 (beta2GP1) and prothrombin, the LA-positive patient sample, and a normal pooled plasma; over 87% of centers correctly identified each sample. However, methods employing platelet neutralizing procedures were associated with a higher proportion of false-negative responses with the antiprothrombin-spiked sample, and it is important to recognize that sensitivity and responsiveness of different methods may vary between artificial plasmas and different LA-positive patient plasmas.

Coagulation Abnormalities in Patients with Noonan Syndrome - a Single Centre Case Series.

Noonan syndrome (NS) is an autosomal dominant disorder that includes short stature, characteristic facies, congenital heart defect, webbed neck, and developmental delay. A mutation in the PTPN11 gene can be identified in 50% of patients. A bleeding tendency is included in the phenotypic spectrum, with factor XI deficiency and platelet abnormalities described most frequently. At Winnipeg's Health Sciences Centre, 24 patients with features typical of NS have been studied by the Special Haemostasis Laboratory. Four patients in whom the diagnosis was suspected but not considered definite are also included in this analysis. Clinical complaints included easy bruising (9), epistaxis (2), menorrhagia (1), and a family history of bleeding problems (3). Sixteen patients were referred for investigation following the diagnosis of NS. All 28 patients had coagulation screening tests: 16 patients had an abnormal PT and 12 had an abnormal aPTT. Thrombin time was slightly prolonged in 6 of 23 patients. Reptilase time was normal in 8 patients, and fibrinogen concentration was normal in 20 patients.Factor XI levels were measured in 14 patients, with a mean value of 62% (range 32–99%). Only 2 patients had levels below the normal range. One of 13 patients evaluated for FXII levels was deficient (FXII 25%), and 2 of 19 patients evaluated for FIX levels had mild FIX deficiency (FIX 40 and 49%) without symptomatic bleeding. No other factor deficiencies were identified. Twenty-four patients had determinations of von Willebrand Factor antigen and activity; 2 had results consistent with mild Type 1 von Willebrand Disease.Platelet aggregation studies were done in 22 patients. A variety of abnormalities were noted, with the most frequent being abnormal aggregation with epinephrine (7/22). Dense granule number was decreased in 2 of 7 samples studied by electron microscopy. Lupus anticoagulants were detected in 3 of 13 patients screened. Thrombophilia investigations in 4 patients detected decreased protein S in one patient who had been diagnosed previously with protein S deficiency.This unselected case series, the largest reported to date in the literature, illustrates the heterogeneity of coagulation abnormalities that may occur in NS. Symptoms, when present, were mild, and often did not correlate with laboratory abnormalities. Non-specific platelet aggregation defects were the most commonly identified abnormalities. In contrast to the literature, factor XI deficiency was not prevalent. A specific etiology for the variable bleeding tendency has not yet been identified in NS.

Clinical Associations and Significance of Biphasic aPTT Transmittance Waveforms.

Many modern automated coagulometers determine coagulation parameters such as the PT and aPTT using optical endpoints. One instrument (MDA-180, BioMerieux, Durham, NC) continuously monitors changes in optical transmittance through the specimen over the course of clot formation, and is able to analyze measurements derived from the resulting waveform. The waveform is typically sigmoid, with a sharp drop in transmittance at the time of clot formation. In some specimens, a biphasic waveform (BPW) pattern has been observed, in which the normally flat pre-coagulation segment has a negative slope prior to the sharp drop in transmittance associated with clot formation. The BPW pattern has been associated with sepsis, DIC, and increased mortality in adult patients. The Special Haemostasis Laboratory of the Health Sciences Centre in Winnipeg, Canada uses the MDA-180 for all automated coagulation assays. Over a two-year period (August, 2002 to July, 2004), a BPW was identified in 21 adult and 12 pediatric patients. Hospital records of these patients were reviewed for details of their clinical condition, and coagulation test results were examined for presence of hemostatic abnormalities. Sepsis was a common diagnosis at the time of detection of the BPW, seen in 57% of the adults and 42% of the children. However, 4 adults (19%) and 4 children (33%) were identified during routine investigations for clinical bleeding or thrombophilia. In contrast to previously reported studies, DIC was less prevalent, seen in only 7 (33%) of the adults and 3 (25%) of the children. The presence of lupus anticoagulants, alone or in conjunction with other coagulation abnormalities, was observed in 8 adults (38%) and 9 children (75%). This association has not previously been reported. Nine adults (43%) and four children (33%) died, all from complications of sepsis. Despite the small sample size, this study questions the clinical utility and specificity of the BPW as an indicator of sepsis and DIC. The association with DIC seems particularly weak in the pediatric population, in which the BPW has not been previously evaluated. Further study is required to determine the strength of the association between the BPW and DIC, and to identify other clinical and laboratory conditions, such as lupus anticoagulants, which may confound this association.

Plasma fibrinogen

Fibrinogen is the major plasma protein coagulation factor. Low plasma fibrinogen concentrations are therefore associated with an increased risk of bleeding due to impaired primary and secondary haemostasis. Fibrinogen is a classical positive acute-phase reactant protein and is an independent predictor of coronary heart disease events. This review considers available methods for measurement of fibrinogen and makes recommendations as to their appropriate use. Total clottable fibrinogen assays are the definitive and reference method for plasma fibrinogen measurement. However, they are time-consuming and are rarely required in clinical practice. Clotting rate assays remain the routine method of choice for investigation, monitoring and treatment of bleeding disorders associated with low plasma fibrinogen concentrations. They are appropriately sited in haematology or haemostasis laboratories, with facilities for further relevant investigations, and expert advice from consultant haematologists on appropriate management. They have also been used in the majority of studies investigating increasing fibrinogen concentrations as a cardiovascular risk factor. Prothrombin-time derived assays are widely used, because they are less expensive and come at no extra cost with prothrombin time assays. However, their results vary widely with analysers and reagents, show discrepancies with clotting rate assays for both low and normal plasma fibrinogen samples, and at present they are not recommended by routine clinical use. Immunoassays (radial immunodiffusion, enzyme-linked immunosorbent assay or nephelometric) are useful in (a) differentiating hypofibrinogenaemia from dysfibrinogenaemia, and (b) assessing cardiovascular risk and acute-phase reactions. Unlike clottable fibrinogen assays, immunoassays can be performed in dipotassium edetate anticoagulated samples.

Evaluation of primary haemostasis in people with neurofibromatosis type 1.

Assessment of haemostasis in people with neurofibromatosis type 1 (NF-1) is essentially lacking, despite case reports of an association with von Willebrand disorder (VWD) and reported excessive bleeding post-surgery. We assessed routine blood haematology, routine coagulation parameters [prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen], coagulation factors II, V, VII, VIII, IX, X, XI and XII, von Willebrand (VWF) factor antigen and activity, and platelet function [using the platelet function analyser (PFA-100)] in a group of individuals with NF-1 (n = 30). Their perceived haemorrhagic bleeding risk was also graded by means of a structured clinical assessment and physical examination. Routine blood assessments including platelet counts were generally normal, as were the routine coagulation tests PT, TT and fibrinogen, and most coagulation factors. Elevated APTTs were detected in 11 individuals, reduced factor XII levels in three, reduced VWF levels in four, and elevated PFA closure times (CTs) in 13. Laboratory results correlated with each other in some but not all cases. For example, elevated APTTs were identified in two of three individuals with a reduced factor XII level and prolonged CTs were identified in three individuals who also showed reduced aggregation responses in classical platelet function studies. Moreover, all individuals with VWF results below the normal reference range showed elevated CTs with both PFA test cartridges, and those with VWF results identified as borderline normal (i.e. 50-65%) also showed elevated CTs with both PFA test cartridges in three of five cases. The relationship between VWF and CTs was also identified by linear regression analysis (P-values of <0.05, for all comparisons). However, as clinically perceived bleeding risk did not appear to be correlated with laboratory test results in most cases, blanket screening of NF-1 individuals for evaluation of laboratory haemostasis may not be warranted.

Platelet function analysis

Since the last guidelines for BCSH platelet function testing were written in the late 1980s, many new tests have become available. Previously most platelet function tests were traditionally utilized to aid in the diagnosis and management of patients with platelet and haemostatic disorders. Most traditional tests were also largely restricted to the specialized laboratory or centre. However, nowadays there is also much renewed interest in monitoring the efficacy of anti-platelet therapy and measuring platelet hyper-function. A number of dedicated platelet function instruments have now become available that are much simpler to use and are beginning to be utilized as point of care instruments. These can now provide measurement of platelet function within whole blood without the requirement of sample processing. Some are also beginning to be incorporated into routine clinical use and can be utilized as not only as general screening tests of platelet function but to monitor anti-platelet therapy and to potentially assess both risk of bleeding and/or thrombosis. Modern flow cytometric-based platelet function analysis now also provides a wide variety of specific tests that can assess different aspects of platelet biology that are useful for diagnostic purposes. This review will highlight some of these of new tests/instruments and discuss their potential utility both within the haemostasis laboratory but also as potential point of care instruments.