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.

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.

ADAMTS-13 glycans and conformation-dependent activity.

Essentials The impact of N-linked glycosylation on ADAMTS-13 function has not been fully explored. The activity of glycan modified ADAMTS-13 was investigated under static and shear stress conditions. Terminal sialic acid on the metalloprotease domain glycans are important for ADAMTS-13 activity. The CUB domain glycans modulate ADAMTS-13 activity. SUMMARY: Background ADAMTS-13 activity can be regulated by its conformation, whereby interactions between the C-terminal CUB domains and the spacer domain maintain ADAMTS-13 in a closed conformation. ADAMTS-13 contains 10 N-linked glycans, with four sites present in theTSP2 through to CUB domains that may contribute to its conformation. Objectives/Methods We hypothesized that glycosylation contributes to ADAMTS-13 conformation and function. The proteolytic activity of glycan-modified ADAMTS-13 was assessed under static and shear stress conditions. Results Enzymatic removal of terminal silaic acid or entire N-linked glycan chains decreased activity against FRETS-VWF73 at pH 7.4 and against full-length von Willebrand factor (VWF) under shear stress. Using truncated ADAMTS-13, we demonstrated that this was attributable to loss of sialic acid from the glycans in the metalloprotease domain and an effect of N-linked glycosylation in the TSP2 through to CUB domains. Mutation of the N-linked glycan sites in the MDTCS domains reduced or abolished protein expression. However, the N707Q, N828Q, N1235Q and N1354Q (TSP2, TSP4, CUB1, and CUB2 domains, respectively) variants were expressed normally. Interestingly, the N707Q and N828Q variants showed reduced activity against FRETS-VWF73, but normal activity under flow conditions. In contrast, the N1235Q and N1354Q variants had enhanced activity against FRETS-VWF73 and VWF under shear stress. Immunoprecipitation experiments confirmed that loss of N-linked glycans in the CUB domains significantly reduced the interaction with the spacer domain and enhanced binding to the 6A6 anti-ADAMTS-13 antibody, which recognizes a cryptic epitope in the metalloprotease domain. Conclusions Together, these data demonstrate that the N-linked glycans of ADAMTS-13 play a crucial role in regulating ADAMTS-13 activity.

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.

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.

A low balance between microparticles expressing tissue factor pathway inhibitor and tissue factor is associated with thrombosis in Behçet's Syndrome.

Thrombosis is common in Behçet's Syndrome (BS), and there is a need for better biomarkers for risk assessment. As microparticles expressing Tissue Factor (TF) can contribute to thrombosis in preclinical models, we investigated whether plasma microparticles expressing Tissue Factor (TF) are increased in BS. We compared blood plasma from 72 healthy controls with that from 88 BS patients (21 with a history of thrombosis (Th+) and 67 without (Th-). Using flow cytometry, we found that the total plasma MP numbers were increased in BS compared to HC, as were MPs expressing TF and Tissue Factor Pathway Inhibitor (TFPI) (all p < 0.0001). Amongst BS patients, the Th+ group had increased total and TF positive MP numbers (both p ≤ 0.0002) compared to the Th- group, but had a lower proportion of TFPI positive MPs (p < 0.05). Consequently, the ratio of TFPI positive to TF positive MP counts (TFPI/TF) was significantly lower in Th+ versus Th- BS patients (p = 0.0002), and no patient with a TFPI/TF MP ratio >0.7 had a history of clinical thrombosis. We conclude that TF-expressing MP are increased in BS and that an imbalance between microparticulate TF and TFPI may predispose to thrombosis.

Site-specific analysis of von Willebrand factor O-glycosylation.

BACKGROUND: O-glycosylation of von Willebrand factor (VWF) affects many of its functions; however, there is currently no information on the occupancy of the 10 putative O-glycosylation sites. OBJECTIVES: The aim of this study was the site-specific analysis of VWF O-glycosylation. METHODS: Tryptic VWF-O-glycopeptides were isolated by lectin affinity chromatography and/or by reverse-phase high-performance liquid chromatography. Subsequently, the purified glycopeptides were analyzed by glycosidase digestion and mass spectrometry. RESULTS: We found that all 10 predicted O-glycosylation sites in VWF are occupied. The majority of the glycan structures on all glycosylation sites is represented by disialyl core 1 O-glycan. The presence of core 2 O-glycan was also confirmed; interestingly, this structure was not evenly distributed among all 10 glycosylation sites. Analysis of the glycopeptides flanking the A1 domain revealed that generally more core-2-type O-glycan was present on the C-terminal Cluster 2 glycopeptide (encompassing T(1468) , T(1477) , S(1486) and T(1487) ) compared with the N-terminal Cluster 1 glycopeptide (encompassing T(1248) , T(1255) , T(1256) and S(1263) ). Disialosyl motifs were present on both glycopeptides flanking the A1 domain and on the glycosylation site T(2298) in the C1 domain. In addition, we identify sulfation of core 2 O-glycans and the presence of the rare Tn antigen. CONCLUSIONS: This is the first study to describe the qualitative and semi-quantitative distribution of O-glycan structures on all 10 O-glycosylation sites, which will provide a valuable starting point for further studies exploring the functional and structural implications of O-glycosylation in VWF.

International Society on Thrombosis and Haemostasis core curriculum project: core competencies in clinical thrombosis and hemostasis.

UNLABELLED: Essentials The priority of ISTH was to establish a global core curriculum in thrombosis and hemostasis. International survey to determine competencies required for clinical specialists was carried out in the field. Competency framework provides a reference point for mapping and developing regional curricula. Core curriculum informs and links to a variety of ISTH educational materials. SUMMARY: Background The International Society on Thrombosis and Haemostasis (ISTH) identified the need for an international core curriculum on thrombosis and hemostasis for its society members and the larger thrombosis and hemostasis community. Aims The current research sought consensus on the core competencies required by medical doctors who are ready to practise as independent clinical specialists in thrombosis and hemostasis with the aim of developing a core clinical curriculum for specialists in the field. Method A draft list of competencies was developed by the Working Group and formed the basis of an online survey. ISTH members and the larger thrombosis and hemostasis community were asked to rate the importance of each competency, on a Likert scale, for clinical specialists in thrombosis and hemostasis. Results There were a total of 644 responses to the online survey with broad geographical representation. There was general agreement on what level of competency would be required for clinical specialists in thrombosis and hemostasis at the specified level of training. Conclusions Using the survey to gain consensus on the level of competency required by clinical specialists in the field of thrombosis and hemostasis enabled the development of a core clinical curriculum that has been endorsed by the ISTH Council. The curriculum will offer a framework and international reference that will be used by the society, by national and regional organizations, and for further research.

Guideline on aspects of cancer-related venous thrombosis

The guideline was drafted by a writing group identified by the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology (BCSH). All the authors are consultants in haematology in the UK. A search was performed of PubMed and Embase using the term 'cancer' combined with 'thrombosis', 'treatment', 'prophylaxis' and 'clinical presentation'. The search covered articles published up until December 2014. Only human studies were included and articles not written in English were excluded. References in recent reviews were also examined. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the BCSH and the BCSH executive. The guideline was then reviewed by the sounding board of the British Society for Haematology (BSH). This comprises 50 or more members of the BSH who have reviewed the guidance and commented on the content and application to the UK setting. The 'GRADE' system was used to quote levels and grades of evidence, details of which can be found at: http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the prevention and management of venous thromboembolism (VTE) in patients with cancer and to advise on an approach to screening for cancer in patients with unprovoked VTE in whom cancer was not initially suspected based on clinical grounds.(AU)

Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial.

BACKGROUND: Prophylaxis with either intravenous (i.v.) factor VIII (FVIII) or FIX is the gold standard of care for patients with severe hemophilia. A monoclonal antibody (concizumab) targeting tissue factor pathway inhibitor (TFPI) that can be administered subcutaneously (s.c.) has the potential to alter current concepts of prophylaxis in hemophilia. OBJECTIVES: To evaluate the safety and describe the pharmacokinetics and pharmacodynamics of single-dose concizumab in healthy volunteers and patients with hemophilia A or B. METHODS: In this first human dose, phase 1, multicenter, randomized, double-blind, placebo-controlled trial escalating single i.v. (0.5-9000 µg kg(-1) ) or s.c. (50-3000 µg kg(-1) ) doses of concizumab were administered to healthy volunteers (n = 28) and hemophilia patients (n = 24). RESULTS: Concizumab had a favorable safety profile after single i.v. or s.c. administration. There were no serious adverse events and no anti-concizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed due to target-mediated clearance. A maximum mean AUC0-∞ of 33 960 h µg mL(-1) and a maximum mean concentration of 247 µg mL(-1) was measured at the highest dose. CONCLUSIONS: Concizumab showed a favorable safety profile after i.v. or s.c. administration and nonlinear pharmacokinetics was observed due to target-mediated clearance. A concentration-dependent procoagulant effect of concizumab was observed, supporting further study into the potential use of s.c. concizumab for hemophilia treatment.

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.

The O-linked glycans of human von Willebrand factor modulate its interaction with ADAMTS-13.

BACKGROUND: O-linked glycans (OLGs) are clustered on either side of the von Willebrand factor (VWF) A1 domain and modulate its interaction with platelets; however, their influence on the VWF interaction with ADAMTS-13 is unknown. OBJECTIVES: To assess the role of the OLGs in VWF susceptibility to ADAMTS-13 proteolysis, which would help to explain their specific distribution. METHODS: OLG sites were mutated individually and as clusters on either and both sides of the A1 domain, and expressed in HEK293T cells. First, their proteolysis by ADAMTS-13 was assayed in the presence of urea. Next, a parallel-flow chamber was used to analyze VWF-mediated platelet capture on collagen in the presence and absence of ADAMTS-13 under a shear stress of 1500 s(-1) . The decrease in platelet capture in the presence ADAMTS-13 was used as a measure of VWF proteolysis. RESULTS: Initially, we found that, under denaturing conditions, the C-terminal S1486A and Cluster 2 and double cluster (DC) variants were less susceptible to ADAMTS-13 proteolysis than wild-type VWF. Next, we showed that addition of ADAMTS-13 diminished VWF-mediated platelet capture on collagen under flow; surprisingly, this was more pronounced with the S1486A, Cluster 2 and DC variants than with wild-type VWF, indicating that these are proteolyzed more rapidly under shear flow. CONCLUSIONS: OLGs provide rigidity to peptide backbones, and our findings suggest that OLG in the A1-A2 linker region regulates VWF conformational changes under shear. Importantly, the impact of OLGs on ADAMTS-13 cleavage under shear stress is the opposite of that under denaturing conditions, highlighting the non-physiologic nature of in vitro cleavage assays.

The von Willebrand factor predicted unpaired cysteines are essential for secretion.

BACKGROUND: von Willebrand factor (VWF) contains free thiols that mass spectroscopy has located to nine cysteines: two in the D3 domain (Cys889 and Cys898) and seven in the C domains (Cys2448, Cys2451, Cys2453, Cys2490, Cys2491, Cys2528, and Cys2533) (J Biol Chem, 7, 2007, 35604; Blood, 118, 5312). It has been suggested that these free thiols function to regulate the self-association of VWF through thiol-disulfide exchange (J Biol Chem, 7, 2007, 35604; Blood, 118, 5312). However, recent structural modeling has predicted that these cysteines are, in fact, disulfide-bonded (Blood, 118, 5312; Blood, 120, 449). OBJECTIVES: To use mutation and expression analyses to investigate how these conflicting reports might be compatible with the synthesis and expression of VWF. METHODS AND RESULTS: Both full-length VWF and VWF fragments with cysteine to alanine mutations of the nine cysteines and two predicted binding partners (Cys2431 and Cys2468) failed to secrete. Mutation of a cysteine pair, C2431A/C2453A, similarly resulted in a failure to secrete, indicating that this is not secondary to creation of an unpaired thiol. Deletion mutants containing seven of these cysteines, conforming to hypothesized domain boundaries, also failed to secrete: ∆C1C6 (2255-2720), ∆C3C4 (2429-2577), ∆C3 (2429-2496), and ∆C4 (2497-2577). Analysis of cell lysates and immunofluorescence confirmed that the mutants were retained within the endoplasmic reticulum (ER). Coexpression with wild-type VWF rescued secretion of some mutants to a limited extent. CONCLUSIONS: These data suggest: first, that pairing of cysteines implicated in free thiol exchange is essential for correct folding of the VWF molecule, and unpairing must occur following exit from the ER or secretion from the cell; and second, that intact C domains are essential for efficient VWF secretion and must interact in the ER.

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.

Severe recurrent achalasia cardia responding to treatment of severe autoimmune acquired haemophilia.

Acquired haemophilia A and severe acquired achalasia are both very rare conditions with unknown aetiology. Haemophilia A is a haemorrhagic disease induced by deficiency or malfunction of coagulation factor VIII. Congenital haemophilia is an inherited disease transmitted by the mother through X-linked inheritance and primarily affects males. However, acquired haemophilia A is a serious, sudden-onset, autoimmune disease that affects either sex. In addition, achalasia is a disease of the oesophagus caused by abnormal function of the nerves and muscles. It causes swallowing difficulties due to the inability of the lower oesophageal sphincter to relax during swallowing, leading to dysphagia, regurgitation and chest pain. In this report, we describe the case of a patient with severe, newly diagnosed, acquired haemophilia A with long-standing, recurrent achalasia; the achalasia had recurred 3 times despite complete and proper surgical fixation. Acquired haemophilia A is treated with immunosuppressive therapy. High-dose steroid therapy was administered for 7 months, during which the patient responded well; moreover, the achalasia did not recur for more than 2 years. The response of the achalasia to immunosuppressive therapy suggests that achalasia may be an autoimmune disorder and that there may be an association between both diseases. The findings of the present case suggest that achalasia may favourably respond to steroid therapy as a first-line treatment prior to surgery.

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.