Survey evaluating clinical equipoise around platelet transfusion after head injury and traumatic intracranial haemorrhage (ICH) in patients on antiplatelet medications.

INTRODUCTION: Patients aged 60 or over account for over half of the severely injured trauma patients and a traumatic brain injury is the most common injury sustained. Many of these patients are taking antiplatelet medications but there is clinical equipoise about the role of platelet transfusion in patients with traumatic intracranial haemorrhage (ICH) taking prior antiplatelet medications. METHOD: A prepiloted survey was designed to explore a range of clinical issues in managing patients taking antiplatelet medications admitted with a traumatic brain injury. This was sent via email to consultants and specialty registrar members of a variety of relevant UK societies and working groups in the fields of emergency medicine, critical care, neurosurgery and haematology. RESULTS: 193 responses were received, mostly from colleagues in emergency medicine, neurosurgery, anaesthesia and haematology. Respondents indicated that there is a lack of evidence to support the use of platelet transfusion in this patient population but also lack of evidence of harm. Results also demonstrate uncertainties as to whether platelets should be given to all or some patients and doubt regarding the value of viscoelastic testing. DISCUSSION: Our survey demonstrates equipoise in current practice with regards to platelet transfusion in patients with a traumatic ICH who are taking antiplatelet medication. There is support for additional trials to investigate the effect of platelet transfusion in this rising population of older, high-risk patients, in order to provide a better evidence-base for guideline development.

Pharmacokinetics, phenotype and product choice in haemophilia B: how to strike a balance?

At the 7th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD) held in Brussels, Belgium, in February 2014, Pfizer sponsored a satellite symposium entitled: "Pharmacokinetics, phenotype and product choice in haemophilia B: How to strike a balance?" Co-chaired by Cedric Hermans (Cliniques Universitaires Saint Luc, Brussels, Belgium) and Mike Laffan (Imperial College, London, UK), the symposium provided an opportunity to debate whether pharmacokinetic (PK) parameters are good surrogates for clinical efficacy for haemophilia B in clinical practice, consider the perceptions and evidence of disease severity, and examine how these considerations can inform approaches to balancing the potential risks and benefits of the currently available treatment options for haemophilia B. PK parameters are routinely measured in clinical practice and are a requirement of regulatory bodies to demonstrate the clinical efficacy of products; however, the relationship between measured PK parameters and clinical efficacy is yet to be determined, an issue that was debated by Gerry Dolan (University Hospital, Queen's Medical Centre, Nottingham, UK) and Erik Berntorp (Lund University, Malmö Centre for Thrombosis and Haemostasis, Malmö, Sweden). Elena Santagostino (Universita degli Studi di Milano, Milano, Italy) reviewed how differing perceptions on the severity of haemophilia B compared with haemophilia A may have an impact on clinical decision-making. Finally, Andreas Tiede (Hannover Medical School, Hannover, Germany), examined the considerations for balancing the potential risks and benefits of the currently available treatment options for haemophilia B. Although the pathophysiology of haemophilia B has been widely studied and is largely understood, continued investigation and discussion around the optimal management course and appropriate therapeutic choice is warranted.

Managing haemophilia for life: 4th Haemophilia Global Summit.

The 4th Haemophilia Global Summit was held in Potsdam, Germany, in September 2013 and brought together an international faculty of haemophilia experts and delegates from multidisciplinary backgrounds. The programme was designed by an independent Scientific Steering Committee of haemophilia experts and explored global perspectives in haemophilia care, discussing practical approaches to the optimal management of haemophilia now and in the future. The topics outlined in this supplement were selected by the Scientific Steering Committee for their relevance and potential to influence haemophilia care globally. In this supplement from the meeting, Jan Astermark reviews current understanding of risk factors for the development of inhibitory antibodies and discusses whether this risk can be modulated and minimized. Factors key to the improvement of joint health in people with haemophilia are explored, with Carlo Martinoli and Víctor Jiménez-Yuste discussing the utility of ultrasound for the early detection of haemophilic arthropathy. Other aspects of care necessary for the prevention and management of joint disease in people with haemophilia are outlined by Thomas Hilberg and Sébastian Lobet, who highlight the therapeutic benefits of physiotherapy and sports therapy. Riitta Lassila and Carlo-Federico Perno describe current knowledge surrounding the risk of transmission of infectious agents via clotting factor concentrates. Finally, different types of extended half-life technology are evaluated by Mike Laffan, with a focus on the practicalities and challenges associated with these products.

Real-world outcomes with recombinant factor VIIa treatment of acute bleeds in haemophilia patients with inhibitors: results from the international ONE registry.

The ONE Registry (OR) was an international prospective observational study of on-demand recombinant factor VIIa (rFVIIa) treatment for mild to moderate bleeds in haemophilia A/B patients with inhibitors. To describe real-world use of single and multi dose rFVIIa and to compare outcomes, including effectiveness, safety, quality of life and treatment satisfaction associated with treatment. Baseline data included demographics, treatment, medical and bleed history and patient/caregiver-reported outcomes regarding bleeds. rFVIIa was prescribed according to routine practice; regimens varied and initial dose was categorized as low (LD, ≤ 120 µg kg(-1) ), intermediate (ID, >120 and <250 µg kg(-1) ) or high (HD, ≥ 250 µg kg(-1) ). OR included 102 patients and 85 (83%) reported 494 bleeds overall. Mean age was 23 years (SD 16.4), with 52% ≥ 18 years. Majority of bleeds (n = 350, 71%) involved ≥ 1 joints; 46% involved a target joint. Median initial dose was 90 µg kg(-1) in LD (range 87-120, n = 156), 174 µg kg(-1) in ID, (range 121-249, n = 127) and 270 µg kg(-1) in HD, (range 250-375, n = 211). For spontaneous bleeds, effective haemostasis rate at 9 h was 63% LD, 60% ID and 56% HD. Rates of combined partially effective/effective haemostasis was 85% LD, 96% ID and 86% HD. Median number of doses in HD was one (range 1-7), compared with two in LD (range 1-17) and ID (range 1-23). No thromboembolic events were reported in 1145 doses given. These observational data in real life are consistent with previous studies which have shown similar overall effectiveness of rFVIIa and similar effectiveness and safety across different patterns of standard initial dosing.

Pregnancy in type 2B VWD: a case series.

Type 2B von Willebrand disease (VWD) is a rare, inherited bleeding disorder resulting from a qualitative defect in von Willebrand factor (VWF). There is very little published information on how to quantify bleeding risk and manage haemostasis in type 2B VWD patients during pregnancy. This article presents the changes in VWF parameters and details of patient management and delivery outcomes for four pregnancies in three women with two different mutations causing type 2B VWD. We report an unexpected rise in the VWF:Ag at 37 weeks gestation in two sisters with R1306W associated with significant thrombocytopenia. These patients were supported with platelet transfusions as well as intermediate purity VWF-FVIII plasma concentrates during the peri- and postpartum periods. No thrombocytopenia was observed in our third case with a mutation encoding an R1308C substitution; haemostatic support was with intermediate purity VWF-FVIII plasma concentrates alone. No adverse bleeding events occurred and in all cases a live healthy infant was delivered. One patient was readmitted post partum with bleeding symptoms due to retained placenta; no further haemostatic support was given at this time. This case series is the first to detail the progression of laboratory parameters, management and outcomes of pregnancy in patients with type 2B VWD. The cases illustrate some of the challenges posed by the increased production of a VWF variant with a gain-of-function effect. The rapid coagulation changes observed in this series illustrate the need for continual monitoring of VWF parameters and platelet count throughout pregnancy in women with type 2B VWD.

von Willebrand's disease: a report from a meeting in the Åland islands.

von Willebrand's disease (VWD) is probably the most common bleeding disorder, with some studies indicating that up to 1% of the population may have the condition. Over recent years interest in VWD has fallen compared to that of haemophilia, partly the result of focus on blood-borne diseases such as HIV and hepatitis. Now the time has come to revisit VWD, and in view of this some 60 international physicians with clinical and scientific interest in VWD met over 4 days in 2010 in the Åland islands to discuss state-of-the-art issues in the disease. The Åland islands are where Erik von Willebrand had first observed a bleeding disorder in a number of members of a family from Föglö, and 2010 was also the 140th anniversary of his birth. This report summarizes the main papers presented at the symposium; topics ranged from genetics and biochemistry through to classification of VWD, pharmacokinetics and laboratory assays used in the diagnosis of the disease, inhibitors, treatment guidelines in different age groups including the elderly who often have comorbid conditions that present challenges, and prophylaxis. Other topics included managing surgeries in patients with VWD and the role of FVIII in VWF replacement, a controversial subject.

Intravenous immunoglobulin increases plasma viscosity without parallel rise in blood pressure.

WHAT IS KNOWN AND OBJECTIVE: Intravenous immunoglobulin (IVIg) is a commonly used therapy for autoimmune disease, but may cause chronic hypertension and thrombosis. We determined whether: (i) IVIg systematically affects blood pressure in the short term; (ii) acute changes in plasma viscosity because of IVIg correlate with blood pressure effects; (iii) effects of IVIg on acute blood pressure are related to baseline blood pressure or hypertension status and (iv) IVIg influences plasma markers of inflammation, anticardiolipin antibodies and homocysteine as additional putative prothrombotic risk factors. METHODS: Twenty adults with autoimmune neurological disease who received a course of IVIg were evaluated immediately before and after each infusion, on every day of the course. Blood pressure, pulse and the following haematological parameters were determined: plasma viscosity, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), haematocrit, fibrinogen, interleukin-6 (IL-6), homocysteine and anticardiolipin positivity. RESULTS: Intravenous immunoglobulin caused both acute and cumulative rises in plasma viscosity across a treatment course, but no concordant changes in blood pressure. There was also no correlation between individual blood pressure changes and viscosity, baseline blood pressure or hypertension status. Levels of IL-6 rose across the course of therapy, but the acute-phase reactants CRP and fibrinogen did not. One patient developed anticardiolipin antibodies during therapy. WHAT IS NEW AND CONCLUSION: Individual courses of IVIg do not systematically raise blood pressure. Where IVIg is found to cause hypertension, this does not appear to be due to a direct effect of IVIg on plasma viscosity.

Non-malignant haematology research in the UK: looking forward to new opportunities.

Over the last few years there has been rapid and radical change in the way clinical research in the UK is funded and supported within the NHS. This has resulted from restructuring and major new investment in research infrastructure, co-ordinated through Clinical Local Research Networks (CLRNs) and equivalent organisations in the devolved nations. CLRNs have resources to support local researchers undertake studies that have been adopted on to the national research portfolio. For example, CLRNs can help with gaining local approvals or provide research nurses to recruit patients, undertake study procedures and perform data entry. CLRNs can establish Local Speciality Groups in a number of areas of medicine, including nonmalignant haematology. These new networks offer non-malignant haematology access to significant new resources and a major opportunity to support clinical research for the benefit of our patients.

Haemopoietic stem cell transplantation induces tolerance to donor antigens but not to foreign FVIII peptides.

A 22-year-old male with severe haemophilia A and high responding factor VIII (FVIII) inhibitor underwent sibling haematopoietic stem cell transplantation in an attempt to eradicate the inhibitor. A reduced intensity conditioning regimen was followed by bone marrow infusion and continuous FVIII administration during immune reconstitution. Although substantial levels of FVIII:C (>100 IU dL(-1)) were maintained initially, at day +23 inhibitor titres rose, indicating boosting of recipient memory repertoire, despite complete donor chimerism. On day +46, he developed Klebsiella pneumoniae septicaemia and died. This case shows that, despite very successful transplantation tolerance, the procedure failed to control long-term memory effector immune cells.

FEIBA prophylaxis in haemophilia patients: a clinical update and treatment recommendations.

In patients with severe haemophilia and inhibitors, regular factor VIII inhibitor bypassing activity (FEIBA) prophylaxis has been shown to reduce the frequency of bleeding by up to 85% and to improve patient quality of life. FEIBA is well tolerated; the incidence of thrombotic events and of allergic reactions is extremely low. The concept of prophylaxis in haemophilia patients with inhibitors is relatively new and some clinicians may be unsure of how to use FEIBA in this context. These treatment recommendations, based on published evidence plus the collective experience of a group of haematologists (with practical knowledge of managing inhibitor patients with FEIBA prophylaxis), are intended to provide guidance to clinicians considering initiating and maintaining patients on FEIBA prophylaxis with specific focus on practical aspects of patient selection, dosing, monitoring and stop criteria.

Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis: a report of seven cases from a regional UK TTP registry.

Thrombotic thrombocytopenic purpura (TTP) may be idiopathic or secondary. We report seven TTP cases precipitated by pancreatitis. The patients were admitted with acute pancreatitis and at that time had no clinical or laboratory features of TTP. The median time to develop TTP after pancreatitis was 3 d. The patients had moderately reduced ADAMTS13 activity (mean activity 49%; normal range 66-126%) with no evidence of anti-ADAMTS13 inhibitory autoantibodies. The median number of plasma exchanges to remission was 10 (range 7-14) and no additional treatment with immunosuppression was required to maintain remission. There have been no relapses to date.

Anomalous rearrangements of the immunoglobulin heavy chain genes in human leukemias support the loop-out mechanism of class switch.

Discrete rearrangements of immunoglobulin genes are characteristic of lymphoproliferative diseases of B cells and provide direct evidence of their clonal nature. In addition, because leukemic transformation and growth may amplify B cell clones regardless of selection by antigen, analysis of rearranged Ig genes in leukemic clones may give insight into molecular events taking place during the ontogenesis of normal B cells. We have tested DNA samples from patients with chronic B cell leukemias in search for abnormal rearrangements of the Ig heavy chain gene region. By Southern blot analysis we found an unexpected break in the JH-C mu region in 7 out of 118 cases. Two of these cases were investigated in detail by constructing from each a phage genomic library and isolating the phage clones containing the break points. In both cases the JH-C mu separation was confirmed. Further analysis demonstrated that in both cases the abnormality was an inversion of the Ig heavy chain gene between C mu and one of the C gamma segments. This inversion structure strongly suggests that, as has been demonstrated in murine cell lines and in splenocytes stimulated in vitro, class switching in human B lymphocytes occurs in vivo via a loop-out deletion mechanism. The frequency of abnormal events may be as high as 15%. Our data indicate that a proportion of cases of chronic B cell leukemia arise from a cell which has attempted an Ig class switch.

Proteolysis of the endothelial cell protein C receptor by neutrophil proteinase 3.

BACKGROUND: The endothelial cell protein C receptor (EPCR) presents protein C to the thrombin:thrombomodulin complex on the endothelium of large vessels, and enhances the generation of activated protein C (APC) and activation of protease-activated receptor-1. A previous report has demonstrated binding of soluble (s) EPCR to activated neutrophils via surface proteinase 3 (PR3). METHODS: We now report further characterization of this interaction. Activated neutrophils and purified PR3 both decrease endothelial cell (EC) surface EPCR, suggestive of its proteolysis. RESULTS: When added to purified recombinant sEPCR, PR3 produced multiple cleavages, with early products including 20 kDa N-terminal and C-terminal (after Lys(176)) fragments. The binding of active site blocked PR3 to sEPCR was studied by surface plasmon resonance. Estimates of the K(D) of 18.5-102 nM were obtained with heterogeneous binding, suggestive of more than a single interaction site. CONCLUSIONS: This work demonstrates PR3 binding to and proteolysis of EPCR and suggests a mechanism by which anticoagulant and cell protective pathways can be down-regulated during inflammation.

Use of recombinant activated factor VII in massive obstetric haemorrhage.

Massive obstetric haemorrhage is a life-threatening emergency that remains a major cause of maternal mortality. Conventional management is aimed at optimising uterine tone, replacing circulating volume and blood products, and surgery to achieve haemostasis. Recently there have been numerous reports of the (unlicensed) use of recombinant activated factor VII in the management of major obstetric haemorrhage. We report our experience of using it in the treatment of major post-partum haemorrhage in four previously healthy parturients. The published reports of recombinant activated factor VII use in post-partum haemorrhage (unrelated to pre-existing coagulopathies) are compared.

Von Willebrand factor and angiogenesis: basic and applied issues.

The recent discovery that von Willebrand factor (VWF) regulates blood vessel formation has opened a novel perspective on the function of this complex protein. VWF was discovered as a key component of hemostasis, capturing platelets at sites of endothelial damage and synthesized in megakaryocytes and endothelial cells (EC). In recent years, novel functions and binding partners have been identified for VWF. The finding that loss of VWF in EC results in enhanced, possibly dysfunctional, angiogenesis is consistent with the clinical observations that in some patients with von Willebrand disease (VWD), vascular malformations can cause severe gastrointestinal (GI) bleeding. In vitro and in vivo studies indicate that VWF can regulate angiogenesis through multiple pathways, both intracellular and extracellular, although their relative importance is still unclear. Investigation of these pathways has been greatly facilitated by the ability to isolate EC from progenitors circulating in the peripheral blood of normal controls and patients with VWD. In the next few years, these will yield further evidence on the molecular pathways controlled by VWF and shed light on this novel and fascinating area of vascular biology. In this article, we will review the evidence supporting a role for VWF in blood vessel formation, the link between VWF dysfunction and vascular malformations causing GI bleeding and how they may be causally related. Finally, we will discuss how these findings point to novel therapeutic approaches to bleeding refractory to VWF replacement therapy in VWD.

Should we abandon the APTT for monitoring unfractionated heparin?

INTRODUCTION: The activated partial thromboplastin time (APTT) is commonly used to monitor unfractionated heparin (UFH) but may not accurately measure the amount of heparin present. The anti-Xa assay is less susceptible to confounding factors and may be a better assay for this purpose. MATERIALS AND METHODS: The validity of the APTT for monitoring UFH was assessed by comparing with an anti-Xa assay on 3543 samples from 475 patients (infants [n=165], children 1-15years [n=60] and adults [n=250]) receiving treatment dose UFH. RESULTS: Overall concordance was poor. The highest concordance (66%; 168/254) was seen in children. Concordance (51.8%) or discordance (48.4%) was almost equal in adult patients. Among adult patients whose anti-Xa level was within 0.3-0.7IU/mL, only 38% had an APTT in the therapeutic range whilst 56% were below and 6% were above therapeutic range. Children and adult patients with anti-Xa of 0.3-0.7IU/mL but sub- therapeutic APTT had significantly higher fibrinogen levels compared to those with therapeutic or supra-therapeutic APTT. CONCLUSIONS: When the anti-Xa level was 0.3-0.7IU/mL, the majority of samples from infants demonstrated a supra-therapeutic APTT, whilst adults tended to have a sub-therapeutic APTT. This may lead to under anticoagulation in infants or over anticoagulation in adults with risk of bleeding if APTT is used to monitor UFH. These results further strengthen existing evidence of the limitation of APTT in monitoring UFH. Discordance of APTT and anti-Xa level in adults and children may be due to elevation of fibrinogen level.

Thromboelastography (TEG®) demonstrates that tinzaparin 4500 international units has no detectable anticoagulant activity after caesarean section.

BACKGROUND: Low molecular weight heparin is routinely used for thromboprophylaxis in pregnancy and the puerperium. Consensus guidelines recommend waiting 10-12h after administration of a thromboprophylactic dose of low molecular weight heparin before performing a neuraxial block or removing an epidural catheter. Thromboelastography (TEG®) has been reported to be sensitive to the effects of enoxaparin 4h after administration. The purpose of this study was to use TEG to examine coagulation changes in the first 10h after a thromboprophylactic dose of tinzaparin in an attempt to ratify the current consensus guidelines about timing of neuraxial blockade and epidural catheter removal. METHODS: Twenty-four women who had undergone caesarean delivery and were classified as low or intermediate risk of thrombosis were recruited. Blood samples were taken before subcutaneous administration of tinzaparin 4500IU, and at 4, 8 and 10h post-dose. Standard TEG analyses were performed using plain and heparinase cuvettes and samples were also sent for laboratory anti-Xa assay. Thromboelastograph profiles were analysed for a low molecular weight heparin effect. RESULTS: Analysis revealed no significant differences in R time, K time, alpha angle or maximum amplitude between plain and heparinase samples at any time point. Apart from a small statistically significant (P=0.033) decrease in maximum amplitude of 2.8% (95% CI 0.3 to 5.4%) at 4h, there were no significant changes in coagulation for any TEG parameter. Anti-Xa levels were virtually undetectable in all patients over the 10h period (median 0.00U/mL; range 0.00-0.13U/mL). CONCLUSION: A thromboprophylactic dose of tinzaparin 4500IU had little detectable effect on coagulation as assessed by TEG and anti-Xa assay. These findings support consensus guidelines which state that it is acceptable to perform neuraxial blockade or remove an epidural catheter 10-12h after a thromboprophylactic dose of tinzaparin. Rather than suggesting a lack of anticoagulant activity, the findings indicate that TEG may not have the sensitivity to detect a tinzaparin effect when this dose is used in this patient group.