Introduction This appraisal considers the 2018 UK Infected Blood Inquiry and its Report (2024) in the context of the history of haemophilia treatment developments over the past fifty-five years, and the tragic impacts of the AIDS pandemic.Aim The paper appraises the conduct and findings of the IBI and its Report in relation to HIV and AIDS.Method This appraisal represents a personal perspective informed by the author's experience from 1969 of treating people with haemophilia and allied blood disorders, and by contemporaneous scientific publications.Results The Report is commended for recommending compensation for infected patients and their families and for recognising developments that enhanced blood safety in the past 50 years. Nevertheless, this appraisal observes that a UK government-backed system of no fault compensation is long-overdue. Failure in the late 1980s to offer one for HIV has prolonged and accentuated the trauma of AIDS for all involved. This perspective hypothesises that in the circumstances under which the IBI was commissioned any belated compensatory award depended on finding culpable responsibility in haemophilia treatment services. The Report's significant omissions, oversights, and judgements with hindsight, were thus deemed necessary to support recommendations for government offers of compensation.Conclusions The Report disappoints in not delivering to patients and their families a more complete, evidence-based history of HIV infection in the context of haemophilia and its treatment. The Report thereby omits acknowledgement of the dedication and professionalism with which members of treatment services collaborated to combat the threats of blood-borne infections.

Hereditary blood coagulation factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder resulting from variants in the gene encoding FVII (F7). Integration of genetic variation with functional consequences on protein function is essential for the interpretation of the pathogenicity of novel variants. Here, we describe the integration of previous locus-specific databases for F7 into a single curated database with enhanced features. The database provides access to in silico analyses that may be useful in the prediction of variant pathogenicity as well as cross-species sequence alignments, structural information, and functional and clinical severity described for each variant, where appropriate. The variant data is shared with the F7 Leiden Open Variation Database. The updated database now includes 221 unique variants, representing gene variants identified in 728 individuals. Single nucleotide variants are the most common type (88%) with missense representing 74% of these variants. A number of variants are found with relatively high minor allele frequencies that are not pathogenic but contribute significantly to the likely pathogenicity of coinherited variants due to their effect on FVII plasma levels. This comprehensive collection of curated information significantly aids the assessment of pathogenicity.

Introduction Advances in genomic sequencing have facilitated the sequencing of genes associated with disorders of haemostasis. The identification of variants within genes and access to curated data incorporating structural, functional, evolutionary as well as phenotypic data has become increasingly important in order to ascribe pathogenicity. Aim The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Database Project aims to provide a single port of entry to a web-accessible resource for variants in genes involved in clinical bleeding disorders. Results New databases have evolved from previously developed single gene variant coagulation database projects, incorporating new data, new analysis tools and a new common database architecture with new interfaces and filters. These new databases currently present information about the genotype, phenotype (laboratory and clinical) and structural and functional effects of variants described in the genes of factor (F) VII (F7), FVIII (F8), FIX (F9) and von Willebrand factor (VWF). Conclusion The project has improved the quality and quantity of information available to the haemostasis research and clinical communities, thereby enabling accurate classification of disease severity in order to make assessments of likely pathogenicity.

This chapter contains sections titled: Introduction European Principles of Hemophilia Care Arrangements for hemophilia care in the UK Current UKHCDO activities Responsibilities of UKHCDO Haemophilia Society Haemophilia Nurses association Haemophilia Chartered physiotherapists Association Social work support Laboratory scientists Haemophilia Alliance Comprehensive hemophilia care in the UK Haemophilia Alliance Service Specification Funding of hemophilia care Future developments in provision of hemophilia care References

Objective—Using a clinical model of deep arterial injury, we assessed the ability of exogenous and endogenous tissue plasminogen activator (t-PA) to limit acute in situ thrombus formation. Approach and Results—Ex vivo thrombus formation was assessed in the Badimon chamber at low and high shear rates in 2 double-blind randomized cross-over studies of 20 healthy volunteers during extracorporeal administration of recombinant t-PA (0, 40, 200, and 1000 ng/mL) or during endogenous t-PA release stimulated by intra-arterial bradykinin infusion in the presence or absence of oral enalapril. Recombinant t-PA caused a dose-dependent reduction in thrombus area under low and high shear conditions (P<0.001 for all). Intra-arterial bradykinin increased plasma t-PA concentrations in the chamber effluent (P<0.01 for all versus saline) that was quadrupled in the presence of enalapril (P<0.0001 versus placebo). These increases were accompanied by an increase in plasma D-dimer concentration (P<0.005 for all versus saline) and, in the presence of enalapril, a reduction in thrombus area in the low shear (16±5; P=0.03) and a trend toward a reduction in the high shear chamber (13±7%; P=0.07). Conclusions—Using a well-characterized clinical model of coronary arterial injury, we demonstrate that endogenous t-PA released from the vascular endothelium enhances fibrinolysis and limits in situ thrombus propagation. These data support a crucial role for the endogenous fibrinolytic system in vivo and suggest that continued exploration and manipulation of its therapeutic potential are warranted.

Hemophilia is a rare disorder that is complex to diagnose and to manage. These evidence-based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion-transmitted infections. By compiling these guidelines, the World Federation of Hemophilia aims to assist healthcare providers seeking to initiate and/or maintain hemophilia care programs, encourage practice harmonization around the world and, where recommendations lack adequate evidence, stimulate appropriate studies.

Microparticles (MPs) are considered to be important biological effectors of several different physiological and pathological processes. There is increasing evidence of their role in haemostasis and thrombosis, and also of their importance in cancer cell survival, invasiveness and metastasis. The level of circulating MPs has been assessed in many different disease states, and there are reports that patients with malignancy and patients with thrombosis have increased levels of circulating MPs and MP-dependent thrombogenic potential. Research into the function and effect of MPs is currently hampered by a lack of standardization in the methods used to identify and quantify them. As these methods improve it is likely that MP assays will be of use both diagnostically and therapeutically in the future.

Objectives. Gynaecological cancer is common. It is highly amenable to effective treatment, but thrombosis remains a common complication. There is controversy about whether microparticles (MPs), particularly tissue factor (TF) positive MPs, are increased in patients with malignancy and/or thrombosis. We therefore set out to investigate the relationship between MPs of different cellular origins, in patients with gynaecological malignancy. We hypothesised that patients with gynaecological malignancy have increased numbers of MPs. We measured MPs released by different cell types in these patients, and correlated the results with measures of haemostatic activation.Methods. We measured the number of platelet-derived MPs (PMPs), endothelial cell-derived MPs (EMPs), leucocyte-derived MPs (LMPs), TF+ve MPs and annexin V (AV) binding MPs in fresh plasma by flow cytometry in patients with gynaecological malignancy and a control group. We also measured D-dimers, prothrombin fragments 1 and 2 (PF1&2) and thrombin-antithrombin (TAT) complexes as indirect markers of haemostatic activation.Results. The number of MPs (from all cell types) was similar in the two patient groups, with no significant differences. The number of circulating TF+ve MPs was also similar between the two groups. D-dimers (p<0.001) and PF1&2 (p = 0.009) were significantly higher in the malignant group reflecting haemostatic activation, but there was no correlation between the level of D-dimers, PF1&2 and TAT and MP numbers.Conclusion. Using fresh samples, MPs were not significantly increased in patients with gynaecological malignancy. There was, however, evidence of haemostatic activation in the patients with malignancy, but no correlation between the number of MPs and haemostatic activation. (C) 2011 Elsevier Inc. All rights reserved.

The guideline group was selected to be representative of UK-based medical experts. MEDLINE and EMBASE were searched systematically for publications in English from 1966 until October 2009 using a variety of key words. The writing group produced the draft guideline which was subsequently revised by consensus by members of the Haemostasis and Thrombosis and Haemato-oncology Task Forces of the British Committee for Standards in Haematology. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the British Committee for Standards in Haematology (BCSH) and the British Society for Haematology Committee and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are as outlined in the Procedure for Guidelines Commissioned by the BCSH (Table I). The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of thrombocytosis in both adult and paediatric patients. The guidance may not be appropriate to all patients with thrombocytosis and in all cases individual patient circumstances may dictate an alternative approach. There is no previous guideline for this topic. The purpose of this guideline is to provide an approach to the diagnosis, investigation and management of patients with a thrombocytosis (i.e., a platelet count >450 × 109/l). This will include advice on how to distinguish reactive thrombocytosis from true haematological disease and how to distinguish essential thrombocythaemia (ET) from other myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) or overlap syndromes. Recommendations for the management of complications of ET, such as splanchnic vein thrombosis, blast crisis and post-ET myelofibrosis are given, as well as advice on management of pregnancy and children with ET. Thrombocytosis is a common finding and is a frequent cause of referral for further investigation. There is a wide range of primary and secondary causes as well as false or ‘spurious’ conditions mimicking thrombocytosis (Table II). Establishing the cause therefore requires consideration of clinical features, haematological parameters, bone marrow aspirate and trephine biopsy morphological features and the presence or absence of clonal genetic abnormalities. The definitions of specific neoplastic entities are guided by diagnostic criteria and algorithms within the world Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues (Swerdlow, 2008). These definitions are based on combinations of clinical and pathological characteristics which may be major (required) or minor (supportive). This most recent iteration of the WHO classification emphasizes the neoplastic nature of the previously termed myeloproliferative diseases and renamed them MPN. The guideline group however discussed and agreed specific diagnostic criteria for ET (Table III) that are subtly different from those of the WHO 2008 classification based upon evidence from the analysis of data from a randomized controlled trial (Wilkins et al, 2008). The diagnostic features, including detailed morphological descriptions of the common myeloid entities associated with thrombocytosis, are provided below and are intended to act as a useful reference to supplement, but not replace, the WHO monograph. The guideline group also developed a diagnostic algorithm to synthesize practice in undertaking the investigation of thrombocytosis (Fig 1). Diagnostic pathway for the investigation of thrombocytosis. *BCR-ABL1 testing is only recommended if there are atypical features on the blood count and/or film (e.g. basophilia). †Bone marrow examination is recommended to confirm the diagnosis, as per the WHO Classification. In some circumstances this may not be clinically indicated. ‡The need for Cytogenetics on the bone marrow should be guided by the blood and bone marrow morphology. The quantification of stromal reticulin fibres and detection of collagen fibrosis are fundamental to the classification and assessment of progression in MPN. Several different semi-quantitative methods for grading reticulin and collagen fibrosis have been developed, ranging from 4 to 6 grades (reviewed in Kuter et al, 2007). The WHO 2008 classification has adopted the European consensus grading scheme (Thiele et al, 2005), developed specifically in the context of MPN trephine histology assessment. This defines four grades, grade 0 being normal and grades 1–3 representing progressive increments above normal. Both grade 2 and grade 3 allow the presence of varying amounts of collagen fibrosis. While the various systems have not been compared in prospective studies, this scheme has the potential advantage of allowing separation of cases with small foci of collagen from those with more extensive fibrosis. A description of this scoring system is illustrated in Fig 2 and in Table IV. Reticulin grading: examples of reticulin stains. A. Grade 0/3 scattered linear reticulin with no intersections (cross-overs) corresponding to normal one marrow; B. Grade 1/3 loose network of reticulin with many intersections, especially in perivascular areas; C. Grade 2/3 widespread and dense increase in reticulin with extensive intersections; D. Grade 3/3 diffuse and dense increase in reticulin with extensive intersections; E. Grade 3/3 coarse bundles of collagen demonstrated; F. Collagen demonstrated using MSB trichrome stain (martius yellow, brilliant crystal scarlet 6R, and soluble blue). All panels original magnification ×40. The most common secondary (or reactive) causes of thrombocytosis are infection, inflammation, iron deficiency, tissue damage, haemolysis, severe exercise, malignancy, hyposplenism and other causes of an acute phase response (Table II). These are usually, but not always, characterized by an elevated C-reactive protein, or erythrocyte sedimentation rate. The platelets are mostly small with a normal mean platelet volume. The blood film may show other features to indicate an underlying cause, including acute infective, or inflammatory, processes. A bone marrow aspirate or trephine is not usually required for reactive thrombocytosis. If one has been performed due to diagnostic uncertainty, this will show megakaryocytic hyperplasia with normal mature and left-shifted megakaryocyte morphology. The megakaryocytes will have a normal interstitial distribution and not show clustering. Reticulin is typically not increased. In chronic infective or inflammatory processes there may also be granulocytic hyperplasia and features of the anaemia of chronic disease. The diagnosis of ET requires a sustained thrombocytosis of >450 × 109/l and the exclusion of reactive causes. The blood film shows a thrombocytosis with varying degrees of platelet anisocytosis. Platelet morphology can vary from those of normal size and granulation to larger atypical forms that may be hypogranular. Features of iron deficiency may be seen if there has been an associated chronic blood loss: while iron deficiency may also mask an underlying polycythaemia vera (PV). Leucoerythroblastosis and poikilocytosis are not seen in ET. An elevated white blood cell count may be detected. Bone marrow examination (aspirate and trephine biopsy) is required according to the WHO classification (Swerdlow, 2008) to make the diagnosis of ET. However, in elderly patients where a clonal marker, such as JAK2 V617F or MPL 515L/K has been detected, without features suspicious of MDS or primary myelofibrosis (PMF), a bone marrow examination may not be necessary. This represents a departure from the WHO classification. However the guidelines group agreed that this was justified for at least two reasons; first, in view of data from the PT-1 histology review demonstrating poor reproducibility in interpreting some trephine biopsy features (Wilkins et al, 2008) and second, that the most recent WHO diagnostic criteria for all stages of PMF requires the presence of additional features such as splenomegaly, leucoerythroblastic film, or significant constitutional symptoms, that bone marrow examination was not always necessary. Nevertheless it is recommended to perform a bone marrow biopsy where there are atypical features, or if during the course of treatment a change in management is planned, such as change of cytoreductive therapy, or if transformation is suspected. The guideline group therefore proposed a modification of the WHO diagnostic criteria for ET (Table III). In ET, the bone marrow is normocellular for age or mildly hypercellular. Megakaryocytes are increased in number and mostly present as single cells; they may form occasional small, loose clusters within the interstitium of the marrow. Large or giant megakaryocytes with hyperlobated (‘staghorn’) nuclei are prominent and these may show increased emperipolesis. The WHO Classification states that large or giant megakaryocytes predominate but smaller forms may also be seen, particularly if immunohistochemistry is used to aid megakaryocyte identification in trephine biopsy sections. Megakaryocytes with normal morphology, including nearly-bare end-stage variants with pyknotic nuclei are also present. This spectrum of megakaryocyte morphology is typical of ET. Erythropoiesis and granulopoiesis are generally normal. Significant dyserythropoiesis and/or dysgranulopoiesis are not features of ET and favour myelodysplasia. Iron stores may be reduced and siderotic granulation is normal. Reticulin is generally not increased (grades 0–2/4 or grade 0/3, depending on the grading system used, see above). A clonal genetic abnormality can be demonstrated in approximately 60% of cases of ET. The JAK2 V617F mutation is detectable in 50% and the MPL mutation in up to 10% (Pardanani et al, 2006; Pikman et al, 2006; Beer et al, 2008; Vannucchi et al, 2008). The presence of the BCR-ABL1 rearrangement (diagnostic of chronic myeloid leukaemia) excludes ET and testing for this should be performed if atypical features are present, such as basophilia, left shift of neutrophils or atypical trephine features. Routine karyotyping is not always required but a karyotypic abnormality where present may be a useful future marker for disease progression. PV is characterized by an elevated haemoglobin, haematocrit and red cell mass, although up to 15% of patients may present with a marked thrombocytosis and clinical features such as pruritis would add weight to a diagnosis of PV. Bone marrow examination (though not always essential) shows a pan-myelosis with normal erythroid and granulocytic differentiation but with spatial disorganisation. In contrast to ET, the megakaryocytes show marked pleomorphism with a higher than normal nuclear:cytoplasmic ratio plus a characteristic mixture of large and small variants; loose clustering of megakaryocyte is usual. The giant megakaryocytes with hyperlobated nuclei that are a feature of ET are not seen in PV. Iron deficiency is common in those patients whose presentation overlaps with ET and should be investigated to exclude a second pathology. The JAK2 V617F mutation is present in more than 97% of PV patients and a further 1–2% will have an exon 12 mutation of JAK2 (Scott et al, 2007),(Pietra et al, 2008). Exon 12 mutations have not been documented in the context of ET or PMF. The ability to discriminate between ET and PV on the basis of trephine evaluation has never been tested, or evaluated in a formal setting. Primary myelofibrosis can present with a marked thrombocytosis, with or without anaemia, teardrop poikilocytosis, leucocytosis and a leuco-erythroblastic blood film. Clinical features again are similar to ET. Platelets tend to show marked anisocytosis with large forms. Bone marrow aspiration may yield a ‘dry tap’ or show hypercellular particles with hypocellular trails. Bone marrow trephine histology shows a spectrum of findings including increased overall cellularity, particularly of granulocytes and megakaryocytes: commonly, there is also reduced erythropoiesis. Granulopoiesis may have a disordered distribution and may be left-shifted but is usually not dysplastic. In PMF the megakaryocytes are markedly abnormal. They have an abnormal distribution and pattern, including adjacency to bone trabeculae and within sinuses. Megakaryocytes may form dense and often large clusters, sometimes forming sheets and have atypical morphology, with the majority being large and having distorted elongated and angular shapes. They have a high nuclear:cytoplasmic ratio and their nuclei are commonly enlarged, hyperchromatic and poorly lobated. Reticulin fibrosis is increased (grade 2/4, grade 1/3 or above) and may be accompanied by overt collagen and/or new bone formation. At its most extreme, there may be markedly reduced haemopoietic cellularity and osteosclerosis. As for ET, the diagnosis of primary myelofibrosis requires the demonstration of a clonal marker (e.g. JAK2 V617F which is present in 50–60% of cases or MPL mutations in 10% (Pardanani et al, 2006; Pikman et al, 2006; Lasho et al, 2006) and the exclusion of PV, chronic myeloid leukaemia (CML) and MDS. Although the 2008 WHO classification includes ‘pre-fibrotic/early stage myelofibrosis’, there is contradictory evidence as to whether this is a distinct entity which requires distinction from ET (Thiele & Kvasnicka, 2003; Gianelli et al, 2006; Wilkins et al, 2008). In the new WHO classification (Swerdlow, 2008) a diagnosis of PMF, whatever the grade, requires the presence of other features, such as splenomegaly, a leucoerythroblastic blood film and constitutional symptoms. This new classification has resolved some uncertainty regarding the classification of patients with thrombocytosis who have increased reticulin fibrosis in the marrow but no other features of PMF – provided such patients have other features consistent with ET they should be managed according to protocols for this condition. The existence of diseases that can demonstrate the clinical and laboratory features of both MDS and a chronic MPN, have been recognized within the WHO Classification of Tumours (Swerdlow, 2008). These entities have been termed the myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN). Care should be taken to ensure that those patients who have a clear history of a preceding myeloproliferative disorder with evidence of subsequent dysplastic transformation, are not included in this group, as the evidence base for their clinical management is different. The MDS/MPN overlap category has been divided into four separate sub-groups: chronic myelomonocytic leukaemia (CMML); atypical CML (aCML); juvenile myelomonocytic leukaemia (JMML); and MDS/MPN, unclassifiable (MDS/MPN-U). Within the latter designation, there has been recognition of the provisional entity of refractory anaemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T). With the exception of RARS-T, where the presence of thrombocytosis is a diagnostic criterion, the other MDS/MPN entities are more commonly associated with thrombocytopenia. JMML is a rare leukaemic disorder of young children, and will not be discussed further in these guidelines. Chromosomal anomalies involving the 3q21–26 locus may be associated with thrombocytosis and should be categorized as MDS unless the blast count is >20%, when the disease is classed as AML (Swerdlow, 2008). Myelodysplastic/myeloproliferative neoplasm; provisional entity – refractory anaemia with ring sideroblasts associated with marked thrombocytosis (RARS-T). This is a provisional entity which has features of both ET and refractory anaemia with ring sideroblasts. Platelet morphology is normal. Red cells are dimorphic and although the majority of cells are normochromic and normocytic, there are small numbers of hypochromic and markedly microcytic cells. The bone marrow (aspirate and trephine biopsy) is hypercellular and shows increased megakaryocytes with morphological features similar to those seen in ET or PMF. Megakaryocyte clustering can be present. There is also increased erythropoiesis with dys-erythropoiesis and ring sideroblasts accounting for more than 15% of late normoblasts. Reticulin varies, from normal to moderately increased. The JAK2 V617F mutation is present in more than 50% of patients (Boissinot et al, 2006; Szpurka et al, 2006). Myelodysplastic Syndrome associated with isolated del(5q). Myelodysplastic syndrome with isolated del(5q) is commonly associated with thrombocytosis (30–50% of patients) and macrocytic anaemia. The platelet morphology is unremarkable whilst the red cells are macrocytic, with mild poikilocytosis and minimal polychromasia. The bone marrow is normocellular, or mildly hypercellular, with dyserythropoiesis. Megakaryocytes are increased in number and are present in the marrow interstitium; they are small or of normal size and have monolobed, or hypolobated nuclei that are characteristically eccentrically placed. Cytogenetic demonstration of del(5q), with loss of bands q31–q33 and without additional complex cytogenetic abnormalities, is required to make the diagnosis. A small number of patients may also have the JAK2 V617F mutation (Ingram et al, 2006). Thrombocytosis is a common finding with a wide range of primary and secondary causes as well as false or ‘spurious’ conditions mimicking thrombocytosis, evaluation of these patients therefore requires a comprehensive approach involving clinical and laboratory parameters The guideline group also developed a diagnostic algorithm to synthesize practice in undertaking the investigation of thrombocytosis (Fig 1). Limitation of life expectancy is a major concern for many patients with ET, especially at the time of diagnosis and unfortunately data on this is scarce and sometimes conflicting (Rozman et al, 1991; Jensen et al, 2000; Passamonti et al, 2004; Wolanskyj et al, 2006). Life expectancy for the first 10 years after a diagnosis of ET is not affected, beyond 10 years the data is less clear. For example, a study from the Mayo clinic involving 322 ET patients followed for a median of 13·6 years, suggested that survival became significantly worse after the first decade (Wolanskyj et al, 2006). However, this evidence from the Mayo clinic study is likely to be influenced by limited knowledge regarding appropriate treatment at that time with use of agents known to increase the risk of leukaemic transformation (Campbell & Green, 2006). In the study by Passamonti et al (2004), ET patients at all ages had a standardized mortality ratio of 1, which was no different from an age- and sex-matched normal population. However, other authors suggest that young patients, who have a longer duration of disease, will accumulate more risk of transformation to myelofibrosis or AML (Passamonti et al, 2004; varez-Larran et al, 2007). Emerging evidence suggests that some patients with ET have a familial component to their disease, although they still appear to have the same risk of vascular complications and evolution to myelofibrosis and AML as classical ET (Rumi et al, 2007). The proposal that various factors may influence prognosis is attractive as this facilitates identification of patients who might be suitable for more aggressive therapies. The major disease-related events that impact upon survival and quality of life for patients with ET are the occurrence of thrombosis, and transformation to leukaemia or myelofibrosis. Fatigue and other constitutional symptoms can also impact upon quality of life and there is data to suggest that these symptoms may be relatively common amongst the MPN patient population (Mesa et al, 2007a), and are therefore worthy of further study. The most frequent complication of ET is thrombosis. For example, in the study reported by Passamonti et al (2004), the rates of thrombosis for ET patients were 12 per 1000 patients years, compared with 1·6 and 1·2 per 1000 patient years for PMF and AML, respectively. Consequently, risk stratification based upon the estimated chance of thrombotic events, has been a useful tool to guide the management of ET. Current risk stratification for thrombosis in ET includes an assessment of age, history of thrombosis, concurrent medical conditions and the platelet count. Some studies suggest that patients aged <60 years and with no prior thrombosis do not show an increased incidence of thrombosis compared to age-matched healthy controls (Ruggeri et al, 1998), in contrast to the findings of other groups (Pearson et al, 1999). Clinical studies suggested that cytoreductive therapy reduced the incidence of thrombosis, which led to the interpretation that this was secondary to a reduction in the platelet count (Cortelazzo et al, 1995; Storen & Tefferi, 2001; Harrison et al, 2005). Paradoxically however, platelet count does not directly correlate with the incidence of thrombosis (Carobbio et al, 2008a) and, furthermore, the difference in the occurrence of thrombotic events in the two arms of the PT-1 trial, despite equivalent control of the platelet counts, suggests that additional factors, such as reduction of haematocrit, leucocyte count or endothelial factors, such as nitric oxide production,are important in the pathogenesis of thrombosis (Harrison et al, 2005). The impact of conventional risk factors for atherosclerosis, including hyperlipidaemia and hypertension, have been assessed in MPN with variable results (Cortelazzo et al, 1990; Besses et al, 1999). Limited work has been specifically performed in ET. Recent recommendations for the management of atherosclerosis suggest that this patient group may benefit from aggressive risk management with the use of antihypertensives and a statin, where appropriate. The utility of routine thrombophilia screening in patients with VTE but without an MPN has been challenged, as it does not usually alter management (Baglin et al, 2003). A single report suggests that F5 R506Q (Factor V Leiden) may be more common in MPN patients with recurrent VTE (Ruggeri et al, 2002), although more studies are needed as F5 R506Q is not a risk factor for recurrence even in patients without an MPN. Furthermore, even if this finding is true, the presence of a genetic thrombophilia is unlikely to alter clinical management of VTE in this context. An increased prevalence of antiphospholipid syndrome (aPL) has been described in ET and is variably associated with an increased risk of both arterial and venous thrombosis (Harrison et al, 2002; Bidot et al, 2005; Robertson et al, 2007). However routine screening for antiphospholipid antibodies is not presently indicated. Patients with persistent antiphospholipid antibodies, or aPL, should be managed according to guidelines for this condition (Greaves et al, 2000). The identification of risk markers for thrombosis is an evolving field and may help to further define risk groups by which to stratify treatment. However any such novel markers should be robust and easily measurable. Some emerging data is discussed below. White blood cell count. In a retrospective study of 143 patients, a normal white blood cell count at presentation (compared to a high count) was associated with a positive influence on symptom-free survival (P = 0·02) in univariate, but not multivariate analysis (Lengfelder et al, 1998). Two recent studies identified that a white blood cell count above 15 × 109/l was associated with thrombotic complications (Wolanskyj et al, 2006; Carobbio et al, 2008b). In latter study, the association of leucocytosis and thrombosis was more evident in the untreated low-risk group, defined as age <60 years with no prior thrombotic event (P = 0·01) (Carobbio et al, 2008b). The potential of the leucocyte count to identify ‘at risk’ patients is attractive but requires a large prospective study. JAK2 V617F. A large number of studies have assessed the impact of the JAK2 V617F mutation upon the clinical phenotype of ET patients. These studies variably identified that JAK2 V617F-positive ET patients had a higher risk of thrombosis. A recent meta-analysis suggests that there was a significant increase in the odds ratio (OR) for thrombosis [OR = 1·83 (95% confidence interval [CI], 1·32–2·53), P < 0·0001], and transformation to PV [OR = 7·67 (95% CI, 2·04–28·87), P = 0·0009] in JAK2 V617F-positive ET patients (Dahabreh et al, 2008), a conclusion confirmed in a second analysis (Lussana et al, 2009). In a study of 260 ET patients, Vannucchi et al (2007) showed that splenomegaly and microvascular symptoms were significantly more common among the small number of ET patients with >50% and 25%JAK2 V617F allele burden, respectively. Increasing mutant allele load also correlated with a higher frequency of arterial thrombosis at diagnosis and this was confirmed in multivariate analysis with a relative risk of 3·0 (95% CI 1·3–6·8; P = 0·01) in patients having a >25% mutant allele burden. However, other groups have not identified this trend, and robust quantitative assays that could corroborate this observation have yet to be validated. MPL mutations. In the PT-1 study, patients with MPL W515 mutations had an increased risk of venous thromboembolism when compared to JAK2 wild-type patients (P = 0·02), although this difference disappeared on multivariate analysis (Beer et al, 2008). In a subsequent study (Vannucchi et al, 2008) the presence of MPL mutations was weakly associated with microvascular disturbance, but not with other thrombotic manifestations. At present, it appears that MPL mutations, which are relatively uncommon in ET, do not add information with regard to prognostic or thrombotic risk. Patients should be stratified according to their risk of thrombotic complications (Evidence level IIa Grade B). The most widely accepted risk stratification is as follows: HIGH RISK Patients who are either >60 years of age OR have had an ET-related thrombotic or haemorrhagic event OR who have a platelet count of >1500 × 109/l. For patients who have no high risk features. This group may be further subdivided by age into: LOW RISK patients <40 years of age with no high risk features, and INTERMEDIATE RISK patients aged 40–60 years with no high risk features Microvascular symptoms are not generally regarded as thrombotic events for the purpose of risk classification but if they are severe or not responding to aspirin the patient could be reclassified as ‘high risk’ (Evidence level IV Grade C). Platelet count per se does not correlate well with thrombotic risk, however, a platelet count >1500 × 109/l has been used as an indicator for cytoreductive therapy in view of the increased haemorrhagic risk (Evidence level III Grade B). In young patients (<40 years) it may be reasonable to use a higher platelet threshold for risk classification in the absence of symptoms. (Evidence level IIa Grade B). The impact of cardiovascular risk factors on thrombotic risk assessment in otherwise low or intermediate risk patients (<60 years and no thrombotic events) remains uncertain. (Evidence level III Grade B). Emerging risk factors include the leucocyte count and JAK2 allele burden, both of which require prospective validation with robust techniques. (Evidence level III Grade C). Two prospective randomized studies that assessed potential treatment strategies for patients with ET have been published. An Italian study randomized 114 high-risk patients (age >60 years or prior thrombosis) between treatment with HC (hydroxyurea) and no cytoreductive agent (Cortelazzo et al, 1995). With a median follow up duration of 27 months, patients on HC suffered statistically fewer thrombotic events. This important study demonstrated that for high-risk patients with ET, cytoreductive therapy with HC reduces vascular complications. The second randomized study is the Medical Research Council (MRC) primary thombocythemia-1 (PT-1) trial (Harrison et al, 2005). In this study, 809 high-risk patients (prior thrombosis, or age >60 years, or hypertension, or diabetes, or platelet count >1000 × 109/l), diagnosed with ET according to the Polycythaemia Vera Study Group (PVSG) criteria (Murphy et al, 1997), were randomized to receive HC plus aspirin or anagrelide plus aspirin. Compared to HC plus aspirin, patients treated with anagrelide plus aspirin suffered higher rates of arterial thrombosis, major haemorrhage and myelofibrotic transformation, but a decreased rate of VTE. These differences occurred despite equivalent control of the platelet count from 6 months after trial entry. These results can be compared with the Italian randomized study. The rate of first thrombosis at 2 years was 4% for those receiving HC in both studies, suggesting the two cohorts of patients were broadly comparable. For the non-HC arms however, the rates of first thrombosis at 2 years were 8% and 26% for patients receiving anagrelide plus aspirin (PT-1) or no cytoreductive therapy (Italian study), respectively. Although such comparisons across studies have their limitations, these data suggest that, for high risk patients, anagrelide plus aspirin provides at least partial protection against arterial thrombosis, but this is not as much as HC plus aspirin for high-risk patients. Two currently running randomized trials will further inform the management of ET. The first is the National Cancer Research Institute study for intermediate risk patients (age 40–60 years; no high risk features) (http://www.ctsu.ox.ac.uk/projects/leuk/pt1). This is a randomized comparison of HC plus aspirin with aspirin alone. It is expected to report in 2011. Until the results of this study are known, treatment guidelines for this intermediate risk group of patients remain poorly evidence-based. The second trial is the ANAHYDRET (ANAgrellde versus HYDRoxyurea in ET) study (http://www.anahydret.at/), which has now reached its target recruitment. This study is powered as a non-inferiority comparison between HC and anagrelide in high-risk

Christopher Ludlam Drug therapy aims to maximize therapeutic efficacy and minimize the risk of harm. Treatment is monitored by patient and physician after its initiation. For individuals with life-long conditions, it is important that the cumulative adverse risks of frequently repeated treatment do not exceed the benefits of long-term therapy. The short-term benefits of therapy may be self evident, whereas the potential accumulation of adverse events may take a long time to become manifest. The time to quantify adverse events may be reduced by surveying and monitoring large numbers of patients, often many thousands of individuals, simultaneously. To do this for a rare disorder such as haemophilia requires extensive, often international, collaboration between haemophilia centres serving patients often living in very different social and environmental conditions. To collect and interpret, these data pose considerable challenges. For most successful surveillance, it is necessary to identify, in advance, potential adverse events which can be ‘logged’, e.g. inhibitor development in haemophilia, but this may overlook new unexpected events, e.g. new infectious agent. The latter has been especially challenging in haemophilia therapy because most of the blood-borne infections are clinically ‘silent’ for prolonged periods. It is therefore especially important to have effective monitoring of potentially infectious agents in the blood-donor community, so that infectious donations do not contribute to the plasma pool from which the clotting factor concentrate is manufactured. In addition to surveillance for expected adverse events, it is also desirable to have some form of ‘open-ended’ monitoring for other events. This is sometimes complicated by it being unclear whether the event is part of the underlying disease process, an alternative medical disorder or a side effect of therapy. One way to collect open-ended data is by recording causes of death. To analyse these, it is often necessary to relate the causes to what is found in the local general population. This can be challenging when the surveyed patients live in different communities in different geographical areas. The challenge, therefore, is to arrange the collection of data that can be interpreted in a way that can be useful in guiding future therapy and managing the underlying medical condition. Some of the current schemes for haemophilia are outlined below. Ideas for improving surveillance, especially using information that is already being collected possibly for other purposes, are also considered. Mark Weinstein The US Advisory Committee on Blood Safety and Availability has defined ‘biovigilance’ as a comprehensive and integrated national patient safety programme to collect, analyse and report the outcomes of collection and transfusion and/or transplantation of blood components and derivatives, cells, tissues and organs [1]. Here, we are using the term pharmacovigilance to apply to plasma dirivatives and their recombinant analogues. To the haemophilia and rare bleeding disorders community, the need for blood product phamacovigilance, and biovigilance which includes haemovigilance is self evident, given the challenges to patient and donor safety we have experienced over the past 30 years. These include problems with donor screening and testing; blood product manufacture; adverse events associated with product administration and receipt and threats of counterfeiting and terrorism. The major focus of haemovigilance programmes in the United States and other countries is to assure the safety and supply of transfusible blood components, including whole blood, platelets, red blood cells and plasma. These products are not pathogen inactivated in the United States, are widely used, have inherent biological variability and are susceptible to shortages based on donor availability. This is not to say that pharmacovigilance with regard to plasma derivatives and recombinant analogues is neglected in any way, but that the expanding scope of haemovigilance activities directed toward blood components is greater, given their wide use and potential to transmit injections diseases. Pharmacovigilance and biovigilance are needed to identify whether an emerging infectious agent is transmissible by a blood product. Examples of biovigilance in this area include identifying and understanding the nature and epidemiology of HIV, West Nile Virus and variant CJD. Through epidemiological studies and before specific tests are developed, biovigilance can help establish donor eligibility and deferral criteria, based on identifying potential sources of pathogen exposure. Once tests are developed to detect the agent, biovigilance can identify how many donors, patients and products are actually exposed to the pathogen, and whether current manufacturing procedures mitigate infectious disease risk. Pharmacovigilance is needed to identify blood derivative products that are contaminated with pathogens or foreign material through failures in product manufacturing or through deliberate acts of counterfeiting or terrorism. For example, biovigilance identified a failure in good manufacturing practices, where patients developed sepsis through receipt of albumin contaminated with bacteria because of cracks in the product vial [2]. Deliberate acts of sabotage include adulteration of immune globulin [3] and heparin [4]. Biovigilance can reveal whether the manufacturing process for a given product is capable of clearing a known or emerging pathogen. As one example of phamacovigilance in this category, examination of adverse event data and reports from a patient organization showed that patients acquired hepatitis A from one brand of factor IX. This led to manufacturing changes in the product that reduced the potential of hepatitis A transmission [5]. Pharmacovigilance can be used to identify products that have an intrinsic defect or cause an unexpected number of adverse events that are unrelated to pathogen contamination or manufacturing deviations. For example, on rare occasions, patients receiving a lot of immune globulin have experienced more than the expected rate of allergic reactions to the product for unknown reasons. Mark Weinstein To address these challenges, pharmacovigilance and biovigilance programmes should provide mechanisms for surveillance, sentinel identification, traceability, exchange of information among stakeholders and analysis and interpretation of data. Biovigilance has many different aspects that involve a variety of data collection methods, analysis and resolution. In the United States, biovigilance programmes are only now becoming centralized. Coordinated safety and public health efforts are shared by various divisions of Health and Human Services agencies including the Food and Drug Administration (FDA), the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH) and Centers for Medicare and Medicaid Services (CMS), with input from trade, academic, industrial and patient groups. In the US, the CDC has the primary responsibility for conducting national disease surveillance and developing epidemiological and laboratory tools to enhance surveillance. CDC’s emerging infectious disease working group gathers information from multiple sources, including state health surveillance, literature reports and reports from regulatory authorities worldwide. CDC shares information about pathogens that might affect blood products with relevant offices within the FDA, and other governmental agencies as appropriate, such as the Department of Defense. FDA assesses the risk of potential pathogen transmission by blood products and develops a risk mitigation strategy depending on the nature of the pathogen. The Centers for Disease Control and Prevention’s National Healthcare Safety Network (NHSN) has worked with the AABB (formerly the American Association of Blood Banks), a trade organization, to develop a web-based haemovigilance system that collects data from hospitals to detect adverse transfusion events such as reactions to blood products, process problems and medical errors. The information, collected using standardized data collection tools, can be used to create benchmarks for trending purposes, provide opportunities for data-driven intervention, including validation, quality control and impact measurement. The first module of this programme, that became operational in February, 2010, is designed to collect information about recipients of blood product transfusions; a second module on blood donors will be implemented shortly. Other CDC surveillance programmes include the Universal Data Collection project to monitor the safety of the nation’s blood supply for persons with bleeding disorders being treated with blood products, as well as to monitor the occurrence of joint complications experienced by persons with haemophilia. CDC also has a programme to monitor for any emergence of Creutzfeldt–Jakob disease. The Food and Drug Administration has a number of different surveillance programmes for blood products that vary according to the type of product under scrutiny, e.g. blood components such as whole blood, cells or plasma, or manufactured products such as plasma derivatives. The Food and Drug Administration leads biovigilance related to blood fatality surveillance for transfusions and donations. A blood collecting or transfusing facility must notify the FDA’s Center for Biologics Evaluation and Research’s (CBER) Office of Compliance and Biologics Quality (OCBQ) when a blood donor or recipient dies, and the death is possibly related to the donation or transfusion. Besides fatality reports, OCBQ receives biological product deviation reports on distributed biological products about any event associated with the manufacturing of blood, blood components or plasma derivatives that deviates from current good manufacturing practices, regulations, standards or specifications that may affect the safety, purity or potency of the product. OCBQ also receives reports about unexpected or unforeseeable events that may affect the safety, purity or potency of these products. Summary results are available at http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/BiologicalProductDeviations The Food and Drug Administration’s postmarketing safety surveillance programme for all approved drug and biological drug products (except blood and blood components) is supported by the Adverse Event Reporting System (AERS), a computerized information database. The FDA receives adverse drug event reports from manufacturers as required by regulation. Additionally, health care professionals and consumers send reports voluntarily through the MedWatch programme. Although MedWatch and AERS are the formal information systems for submitting suspected side effect reports to FDA, such information occasionally comes to light through other channels. Examples include direct informal consumer or health care professional contact with FDA’s Office of Communication, Outreach and Development (OCOD) or clinical trial data received by the Office of Blood Research and Review. The Food and Drug Administration also collects information from large data sources such as CMS claims data, the Department of Defense and the Veterans Administration among others. FDA’s Sentinel Initiative that is currently under development will strengthen FDA’s ability to monitor postmarket product performance by expanding our access to existing automated healthcare data. Information from large data sources is used for biological product safety hypothesis testing and surveillance within defined populations. One example of the use of survey information from large databases might be examining CMS claims data for the occurrence of Transfusion Related Acute Lung Injury (TRALI) among US elderly inpatients. Non-governmental organizations such as AABB, the Plasma Protein Therapeutics Association and the American Thrombosis and Hemostasis Network also have a role in monitoring and reporting adverse events. Efforts are now underway to expand our surveillance capability and increase cooperation amongst stakeholders. In Canada, the Transfusion Transmitted Injuries Surveillance System (TTISS) of the Public Health Agency of Canada (PHAC) collects haemovigilance data. Hospitals report adverse incidents to provincial/territorial blood offices on standard forms, using standard definitions. The local offices report a subset of data to the PHAC that excludes minor incidents and incorrect blood component transfusion information. The PHAC also receives voluntary and mandatory reporting information, including deaths and severe reactions from plasma and blood manufacturers. The PHAC validates the data, assuring completeness and accuracy and compliance with standard definitions. An analysis of the data is reported annually. It includes information about adverse transfusion events by type of product, number of blood components transfused, diagnosis of adverse transfusion events by type of blood component or plasma derivative and fatalities. Mike Makris The demonstration of safety of the treatments relies on pharmacovigilance, a term used to describe surveillance, monitoring and investigation of adverse drug reactions. The two main aspects of pharmacovigilance are: Voluntary reporting by health professionals (and patients) to regulatory authorities. This ideal is not however often followed, and some of the reasons for this failure are outlined in Table 1. Without an established process, voluntary reporting of adverse events in haemophilia has so far not worked well. Currently available reporting schemes such as Serious Hazards of Transfusion (SHOT) and Serious Adverse Blood Reactions and Events (SABRE) record only events in relation to unfractionated plasma products and specifically exclude clotting factor concentrates. Mandatory reporting from manufacturers. Formal studies evaluating new concentrates in terms of efficacy and safety required to obtain marketing authorisation involve small numbers of patients followed for a short period of time. The usage of these concentrates in real-life situations involves large numbers of patients of different ethnic and genetic backgrounds using the products over many years. Postmarketing surveillance studies are required to document frequent as well as rare adverse effects that may escape or fail to reach statistical significance in small cohort studies. Most postmarketing pharmacovigilance studies in haemophilia initiated by manufacturers have also been small, rarely recruiting more than a hundred patients. In Europe, the Paediatric Network for Haemophilia Management (PEDNET) is a group of 23 European paediatricians who since 2000 are enrolling all their new patients with haemophilia and following them prospectively for the development of inhibitors. The number of patients enrolled, however (250) is relatively small [6]. The primary aim of this group is to identify the incidence of inhibitors in untreated patients and investigate the role of factors in their development. While this is the most intensively studied group of patients, the number involved is relatively small. The only sizeable surveillance project in Europe currently is the UK Haemophilia Centre Doctors Organisation (UKHCDO) national database that only covers the UK. For the last 20 years, there has been a paper-based surveillance system for regular reporting of inhibitors, thromboses and infections. The only analysis performed and reported on from this surveillance system concerned the development of inhibitors [7]. The problem with this national system is that the introduction of national contracting has meant that all patients will be exposed to only a very limited number of concentrates and the value of the surveillance will thus be limited. The only other European country with a central AERS is the Netherlands, but no data from this system have been formally reported. No central haemophilia AERS is available in the other European Countries. Recently, a European AERS called European Haemophilia Surveillance System (EUHASS) has been initiated. European Haemophilia Surveillance System is a prospective adverse and serious event reporting system. A total of 56 haemophilia centres caring for 18 000 patients with inherited bleeding disorders in 27 European countries are taking part. The system is electronic, in English, and events are reported live as they occur or 3 monthly at the latest. The reported events are allergic/acute reactions, transfusion transmitted infections, inhibitors, thromboses, malignancies and deaths. As centres report data on the exposed population, incident rates can be calculated. In the first year of surveillance, 167 events have been reported. A total of 56 different clotting factor concentrates were used in the participating centres. EUHASS has the potential to provide pharmacovigilance information on large numbers of exposed persons with inherited bleeding disorders. As this is a dynamic cohort, a new method has been developed to calculate the inhibitor risk in patients with <50 exposures. Further information on EUHASS can be found at the project website http://www.euhass.org. Mark Weinstein The World Health Organization (WHO) is interested in developing a global haemovigilance network. In December 2007, the WHO Global Collaboration for Blood Safety (GCBS) met and agreed on the need to support such a network. A global consortium consisting of WHO, Canada, International Society of Blood Transfusion, European Haemovigilance Network and the USPHS agreed to form a multilateral steering committee to support collaborative efforts and develop a work plan. The Global Steering Committee for Haemovigilance (GloSCH) will: ‘provide an ongoing, international forum to develop and promote global haemovigilance; function as a forum for dialogue, advice and information gathering; promote standardized global haemovigilance reporting tools and determine whether these tools are useful and relevant; and share information concerning haemovigilance data among member organizations.’ The GloSCH is currently working on two documents: ‘Development of WHO Recommendations on Establishment of National Haemovigilance Systems’; and a technical and/or guidance document to support standardization of haemovigilance reporting. The EUHASS project has received funding from the European Union, in the framework of the Public Health Programme. Dr. Peter Gancz, Director, Centre for Biologics Evaluation, Biologics and Genetic Therapies, Health Canada, has kindly provided information about the haemovigilance in Canada, and the work of GCBS. For M. Weinstein, the findings and conclusions in this presentation have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy.

OBJECTIVE To examine the effects of acute insulin-induced hypoglycemia on inflammation, endothelial dysfunction, and platelet activation in adults with and without type 1 diabetes. RESEARCH DESIGN AND METHODS We studied 16 nondiabetic adults and 16 subjects with type 1 diabetes during euglycemia (blood glucose 4.5 mmol/l) and hypoglycemia (blood glucose 2.5 mmol/l). Markers of inflammation, thrombosis, and endothelial dysfunction (soluble P-selectin, interleukin-6, von Willebrand factor [vWF], tissue plasminogen activator [tPA], high-sensitivity C-reactive protein [hsCRP], and soluble CD40 ligand [sCD40L]) were measured; platelet-monocyte aggregation and CD40 expression on monocytes were determined using flow cytometry. RESULTS In nondiabetic participants, platelet activation occurred after hypoglycemia, with increments in platelet-monocyte aggregation and P-selectin (P ≤ 0.02). Inflammation was triggered with CD40 expression increasing maximally at 24 h (3.13 ± 2.3% vs. 2.06 ± 1.0%) after hypoglycemia (P = 0.009). Both sCD40L and hsCRP (P = 0.02) increased with a nonsignificant rise in vWF and tPA, indicating a possible endothelial effect. A reduction in sCD40L, tPA, and P-selectin occurred during euglycemia (P = 0.03, P ≤ 0.006, and P = 0.006, respectively). In type 1 diabetes, both CD40 expression (5.54 ± 4.4% vs. 3.65 ± 1.8%; P = 0.006) and plasma sCD40L concentrations increased during hypoglycemia (peak 3.41 ± 3.2 vs. 2.85 ± 2.8 ng/ml; P = 0.03). Platelet-monocyte aggregation also increased significantly at 24 h after hypoglycemia (P = 0.03). A decline in vWF and P-selectin occurred during euglycemia (P ≤ 0.04). CONCLUSIONS Acute hypoglycemia may provoke upregulation and release of vasoactive substances in adults with and without type 1 diabetes. This may be a putative mechanism for hypoglycemia-induced vascular injury.

Disorders of either the hemostatic system or the bone marrow may lead to impaired musculoskeletal development.

Objective: Pregnancy is associated with marked changes in vascular physiology and an increased risk of thrombosis. The aim of the study was to assess the effect of pregnancy on the acute release of tissue plasminogen activator (t-PA) from the endothelium. Methods and results: Ten primigravida pregnant women were recruited in the third trimester of pregnancy (week 36 +/- 1) and compared with 20 age-matched non-pregnant women (day 9.8 +/- 0.3 of menstrual cycle). Blood flow and plasma fibrinolytic factors were measured in both forearms by venous occlusion plethysmography and blood sampling, respectively, during unilateral brachial artery infusions of bradykinin (100-1000 pmol min(-1)). Pregnant women had higher plasma plasminogen activator inhibitor type 1 (PAI-1) antigen concentrations (77.1 +/- 12.4 vs. 21.5 +/- 9.8 ng mL(-1); P = 0.004) that resulted in lower basal t-PA/PAI-1 ratios (0.2 +/- 0.1 vs. 0.6 +/- 0.1; P = 0.02) and plasma t-PA activity concentrations (0.17 +/- 0.02 vs. 0.58 +/- 0.06 IU mL(-1); P < 0.0004). In both groups, bradykinin caused dose-dependent increases in blood flow and local release of plasma t-PA antigen and activity (P < 0.005 for all). Both the plasma t-PA/PAI-1 ratios and the net release of active t-PA were markedly reduced in pregnant women (P < 0.05 for both). Area under the curve for net active t-PA release was reduced by 36%. Conclusions: Pregnancy is associated with major perturbations of endogenous fibrinolytic capacity with an overwhelming increase in plasma PAI-1 concentrations and an inadequate release of active t-PA. These prothrombotic effects may, in part, explain the increased risk of arterial and venous thrombosis in pregnant women.

Patients with haemophilia complicated by inhibitors have a significant burden of joint disease, which is associated with a negative impact on their quality of life. Successful elective orthopaedic surgery can result in decreased bleed frequency into a new joint, less time spent in hospital, increased mobility and improved well being. This paper describes a new protocol for use of recombinant activated factor VII (rFVIIa) in elective orthopaedic surgery, based on a review of published data as well as the personal experience of a group of expert physicians. The protocol offers guidance on the planning of the surgery and preoperative testing as well as the bolus schedule for rFVIIa and advice on the concomitant use of antifibrinolytic agents and fibrin sealants. A total of 10 operations involving 13 procedures in eight patients in five comprehensive care centres have been undertaken until now using the protocol, which employs an initial bolus dose of rFVIIa in the range of 120-180 microg kg(-1) to cover surgery. The clinical experience reported here encompasses all cases of elective orthopaedic surgery using rFVIIa as initial treatment carried out in the UK and Republic of Ireland over the last 2 years. In all cases, there was good control of haemostasis during surgery and the final outcome was rated as 'excellent' or 'extremely satisfactory' by the reporting clinicians. Although the initial cost of product to cover surgery such as arthroplasty is high, it needs to be borne in mind that this may be offset in subsequent years by savings resulting from avoidance of bleeding episodes in the affected joint.

Rationale Cardiovascular disease is a major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD), which may in part be attributable to abnormalities of systemic vascular function. It is unclear whether such associations relate to the presence of COPD or prior smoking habit.Objectives: To undertake a comprehensive assessment of vascular function in patients with COPD and healthy control subjects matched for smoking history.Methods: Eighteen men with COPD were compared with 17 healthy male control subjects matched for age and lifetime cigarette smoke exposure. Participants were free from clinically evident cardiovascular disease.Measurements and Main Results: Pulse wave velocity and pulse wave analysis were measured via applanation tonometry at carotid, radial, and femoral arteries. Blood flow was measured in both forearms using venous occlusion plethysmography during intrabrachial infusion of endothelium-dependent vasodilators (bradykinin, 100-1,000 pmol/min; acetylcholine, 5-20 mu g/min) and endothelium-independent vasodilators (sodium nitroprusside, 2-8 mu g/min; verapamil, 10-100 mu g/min). Tissue plasminogen activator (t-PA) was measured in venous plasma before and during bradykinin infusions. Patients with COPD have greater arterial stiffness (pulse wave velocity, 11 +/- 2 vs. 9 +/- 2 m/s; P = 0.003; augmentation index, 27 +/- 10 vs. 21 +/- 6%; P = 0.028), but there were no differences in endothelium-dependent and -independent vasomotor function or bradykinin-induced endothelial t-PA release (P > 0.05 for all).Conclusions: COPD is associated with increased arterial stiffness independent of cigarette smoke exposure. However, this abnormality is not explained by systemic endothelial dysfunction. Increased arterial stiffness may represent the mechanistic link between COPD and the increased risk for cardiovascular disease associated with this condition.