A calcium-containing electrolyte-balanced hydroxyethyl starch (HES) solution is associated with higher factor VIII activity than is a non-balanced HES solution,but does not affect von Willebrand factor function or thromboelastometric measurements - results of a model of in vitro haemodilution

Background

Hydroxyethyl starch (HES) is known to impair blood coagulation. The impact of calcium-containing, balanced carrier solutions of HES on coagulation is controversial. We investigated the effects of increasing degrees of haemodilution with modern 6%, electrolyte-balanced HES vs non-balanced HES on coagulation in vitro, and compared the balanced HES to a balanced crystalloid solution for an internal control.

Materials and methods

Blood samples from ten healthy volunteers were diluted in vitro by 20%, 40% and 60% with either calcium-containing balanced 130/0.42 HES, non-balanced 130/0.4 HES or balanced crystalloid. In all samples, blood counts, prothrombin time ratio, activated partial thromboplastin time, ionized calcium, factor VIII activity, von Willebrand factor antigen, von Willebrand factor collagen binding activity, and von Willebrand factor activity were determined, and activated rotational thromboelastometry (EXTEM and FIBTEM assays) was performed.

Results

Haemodilution impaired coagulation in a dilution-dependent manner as determined by both conventional laboratory assays and thromboelastometry. Ionized calcium increased with balanced HES (p≤0.004), but decreased with non-balanced HES (p≤0.004). Prothrombin time ratio (p≤0.002) and factor VIII levels (p=0.001) were better preserved with balanced HES than with non-balanced HES in dilutions ≥40%. Thromboelastometry showed no differences between values in blood diluted with the balanced or non-balanced HES.

Discussion

In vitro, a balanced calcium-containing carrier solution of 6% HES 130/0.42 preserved coagulation better than did non-balanced HES 130/0.4 as quantified by conventional coagulation assays, but not in activated thromboelastometry. One explanation could be the increased ionized calcium levels after dilution with calcium-containing carrier solutions.     

Influence of intravascular molecular weight of hydroxyethyl starch on platelets

Abstract: Complications concerning the blood coagulation have been observed repeatedly after administration of highly substituted, high molecular weight hydroxyethyl starch (HES), but it has not been examined as to how intravascular molecular weight and degree of substitution of HES influence platelet number and volume after repeated administration. Thirty patients with cerebrovascular diseases were treated for 10 days with hemodilution. 500 to 1500 ml of HES 200/0.62 (n = 10), HES 200/0.5 (n = 10) or HES 40/0.5 (n = 10) were infused daily. During the first days, the number of platelets was not lowered beyond the dilution effect, but at the end of the therapy the number of platelets had increased in all 3 groups beyond the initial value. Platelet volume was lowered significantly in the 3 groups. HES 200/0.62 caused the largest drop in platelet volume (-10%, p<0.01). A possible explanation could be that HES macromolecules are attached to platelets or are phagocytized by them. The larger platelets are then broken down and, to compensate the loss, more thrombocytes are released. A correlation between the molecular weight of HES and the breakdown rate of the platelets can be suspected, because HES 200/0.62 had the highest intravascular mean molecular weight (121 kD) and the largest effect on platelet volume.     

Hydroxyethyl starch induced acquired von Willebrand's disease.

Hydroxyethyl starch (HES) (Hespan, DuPont) is a widely used synthetic volume expander which in standard doses of up to 1.5l in 24 h has no significant effect on coagulation (Munsch et al. 1988). However, the data sheet states that in large volumes HES may alter the coagulation mechanism. We now report a case of HES induced acquired von Willebrand's disease (vWD) in which severe bleeding occurred.     

Hypereosinophilic syndrome with DIC treated successfully with a combination of high-dose methylprednisolone and cyclosporin A]

A 47-year-old man was admitted to our hospital with subcutaneous nodules on the bilateral lower legs and disseminated intravascular coagulation (DIC). Peripheral blood examination revealed leukocytosis with an increase of mature eosinophils, thrombocytopenia and abnormal coagulation. Bone marrow aspiration revealed an increased eosinophil count, and a diagnosis of hypereosinophilic syndrome (HES) was made. Prednisolone (PSL) therapy was not effective. Subsequent methylPSL pulse therapy followed by PSL brought about a transient improvement of the HES and DIC, but after reduction of the PSL, the HES worsened. After addition of cyclosporin A to the PSL, however, the HES improved and did not worsen.     

Comparative Effects of Tetragastrin and Histamine on Pepsin Secretion in Man

Abstract

Objectives. Restoration of the macro- and microcirculation is important for the healing of gastrointestinal anastomoses. Colloids and crystalloids are widely used for blood volume therapy. We evaluated the effects of human albumin, hydroxyethyl starch (HES) 130/0.4 and saline on the microcirculation and on wound healing in colon anastomoses in rats. Material and methods. Male Wistar rats received a colonic end-to-end anastomosis. The animals were randomized into three groups and a single 3-ml dose of either 20% human albumin, 6% HES 130/0.4 or 0.9% saline was applied intravenously. Six, 24, 48, 96 h and 2 weeks after the procedure, 10 animals per group were reanesthetized. Measurements of capillary blood flow, vessel permeability and anastomosis bursting pressure were performed. The amounts of vascular endothelial growth factor (VEGF) and IL-6 in the plasma were determined by enzyme-linked immunosorbent assays, and the mRNA levels of VEGF and collagen types I and III were measured by real-time polymerase chain reaction. Results. No significant differences were found between albumin, HES 130/0.4 and saline in capillary blood flow, vessel permeability and anastomotic bursting pressure in this rat model. Concentrations of collagen I and III mRNA were significantly elevated after 96 h in animals that had received HES 130/0.4 or albumin. RNA and protein levels of VEGF and interleukin-6 were unaffected by therapy. Conclusions. Human albumin, which is still widely used in the clinical setting, had no advantage over HES 130/0.4 and saline with regard to anastomotic healing in this animal model. Nevertheless, we prefer HES 130/0.4 because it is more effective for volume therapy than saline and has a better availability and is less expensive than human albumin.     

World Health Organization-defined eosinophilic disorders: 2012 update on diagnosis, risk stratification, and management

Disease overview: The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end‐organ damage. Diagnosis: Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm³ and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ‐hybridization, flow immunocytometry, and T‐cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. Risk stratification: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semimolecular classification scheme of disease subtypes including “myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1,” chronic eosinophilic leukemia, not otherwise specified' (CEL, NOS), lymphocyte‐variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. Risk‐adapted therapy: The goal of therapy is to mitigate eosinophil‐mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1,500/mm³) without symptoms or signs of organ involvement, a watch and wait approach with close‐follow‐up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first‐line therapy for patients with lymphocyte‐variant hypereosinophilia and HES. Hydroxyurea and interferon‐alpha have demonstrated efficacy as initial treatment and steroid‐refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL‐5 (mepolizumab) and anti‐CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.     

Impact of experimental haemodilution on platelet function,thrombin generation and clot firmness: effects of different coagulation factor concentrates

Background

Haemodilution during resuscitation after massive haemorrhage may worsen the coagulopathy and perpetuate bleeding.

Materials and methods

Blood samples from healthy donors were diluted (30 and-60%) using crystalloids (saline, Ringer’s lactate, Plasmalyte^TM) or colloids (6% hydroxyethylstarch [HES130/0.4], 5% human albumin, and gelatin). The effects of haemodilution on platelet adhesion (Impact R), thrombin generation (TG), and thromboelastometry (TEM) parameters were analysed as were the effects of fibrinogen, prothrombin complex concentrates (PCC), activated recombinant factor VII (FVIIa), and cryoprecipates on haemodilution.

Results

Platelet interactions was already significantly reduced at 30% haemodilution. Platelet reactivity was not improved by addition of any of the concentrates tested. A decrease in TG and marked alterations of TEM parameters were noted at 60% haemodilution. HES130/0.4 was the expander with the most deleterious action. TG was significantly enhanced by PCC whereas rFVIIa only caused a mild acceleration of TG initiation. Fibrinogen restored the alterations of TEM parameters caused by haemodilution including those caused by HES 130/0.4. Cryoprecipitates significantly improved the alterations caused by haemodilution on TG and TEM parameters; the effects on TG disappeared after ultracentrifugation of the cryoprecipitates.

Discussion

The haemostatic alterations caused by haemodilution are multifactorial and affect both blood cells and coagulation. In our in vitro approach, HES 130/0.4 had the most deleterious effect on haemostasis parameters. Coagulation factor concentrates did not improve platelet interactions in the Impact R, but did have favourable effects on coagulation parameters measured by TG and TEM. Fibrinogen notably improved TEM parameters without increasing thrombin generation, suggesting that this concentrate may help to preserve blood clotting abilities during haemodilution without enhancing the prothrombotic risk.     

Citrate artificially masks the haemostatic effect of recombinant factor VIIa in dilutional coagulopathy

Most often, thrombelastographic analyses are carried out using citrated blood and re-calcification. However, calcium chelation may affect dynamics of tissue-factor-initiated thrombin generation. The present study investigates the effect of sample anticoagulant on the response of a colloid induced dilutional coagulopathy model to recombinant activated factor VII (rFVIIa) as measured by thrombelastography. Thrombelastographic evaluation of whole blood coagulation activated with minute amounts of tissue factor in a model of in vitro haemodilution with hydroxyethyl starch (HES) 130/0.4 in a prospective laboratory study. Whole blood coagulation was evaluated before and after 30% dilution with HES 130/0.4, and following in vitro addition of rFVIIa to whole blood collected into tubes containing citrate, corn trypsin inhibitor (CTI), and no stabilizers. Haemodilution with HES 130/0.4 induces a coagulopathy characterised by a reduced maximum rate of clot formation and a pronounced reduction in the final clot firmness. With all test mediums investigated, rFVIIa significantly shortened clot initiation phase. In cases of native whole blood and CTI-stabilised whole blood, rFVIIa shortens the clotting time but also demonstrated an acceleration of the maximum velocity of clot formation. When citrate is used as anticoagulants in thrombelastographic clotting assays, these may artificially mask the haemostatic effect of rFVIIa in colloid haemodilution. The effect in vitro of rFVIIa in citrated blood samples may underestimate the haemostatic potential of rFVIIa. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

World Health Organization‐defined eosinophilic disorders: 2015 update on diagnosis,risk stratification,and management

Disease overview : The eosinophilias encompass a broad range of non‐hematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end‐organ damage. Diagnosis : Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm³ and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ‐hybridization, flow immunocytometry, and T‐cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. Risk stratification : Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semi‐molecular classification scheme of disease subtypes including ‘myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1’, chronic eosinophilic leukemia, not otherwise specified, (CEL, NOS), lymphocyte‐variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. Risk‐adapted therapy : The goal of the therapy is to mitigate eosinophil‐mediated organ damage. For patients with milder forms of eosinophilia (e.g. < 1,500/mm³) without symptoms or signs of organ involvement, a watch and wait approach with close‐follow‐up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first‐line therapy for patients with lymphocyte‐variant hypereosinophilia and HES. Hydroxyurea and interferon‐alpha have demonstrated efficacy as initial treatment and steroid‐refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL‐5 (mepolizumab) and anti‐CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established. Am. J. Hematol. 90:1077–1089, 2015. © 2015 Wiley Periodicals, Inc.     

Natural history of severe eosinophilia with uncertain aetiology and proposals on a practical approach to its management

Background: Eosinophilia is commonly encountered during clinical practice. Some can be attributed to well‐defined causes while others cannot. Optimal management of hypereosinophilia with unknown aetiology is uncertain as the natural history is not well described. Methods: We retrospectively studied patients with hypereosinophilia (>5 × 10⁹/L) and described the characteristics, natural history and treatment of those with eosinophilia of uncertain aetiology. Results: There were 141 patients with hypereosinophilia: 87 with well‐defined causes, 54 with uncertain aetiology. The latter was managed as hypereosinophilic syndrome (HES) (n= 5), idiopathic hypereosinophilia (IH) (n= 11), presumptive helminthic infection (n= 11) and reactive eosinophilia (n= 5), while 22 were insufficiently investigated and did not have definite working diagnoses. Their median age and peak eosinophil count were 64 (22 to 94) years and 10.0 (5.2–33.9) × 10⁹/L respectively. Forty‐six per cent had symptoms attributable to eosinophilia, with the HES and insufficiently investigated groups having the highest (100%) and lowest (27%) percentages respectively. HES and IH patients were most extensively investigated. All 14 HES or IH patients who received steroids responded. All presumptive helminthic infection patients received mebendazole: nine responded, and two had unassessable responses. For the remaining patients, seven received steroids and all responded; one received mebendazole but defaulted; 19 were not treated:11 resolved spontaneously. No non‐HES patients developed eosinophilia‐related organ dysfunction. No mortality was caused by hypereosinophilia. Conclusions: Patients with hypereosinophilia of uncertain aetiology can be empirically managed according to working diagnoses derived from history taking, examination and selective investigations. Most patients have benign short‐term outcomes, but longer monitoring is required to assess long‐term outcomes from untreated hypereosinophilia.     

Increased eosinophil colony formation in agar by haemopoietic cells from patients with the hypereosinophilic syndrome

Summary Colony formation by granulocyte/macrophage and eosinophilic progenitor cells in the blood and/or bone marrow of four patients with ‘hypereosinophilic syndrome’ (HES) was studied in agar culture. Colony-stimulating activity (CSA) was derived from leucocyte feeder layers (LFL) or from medium conditioned by phytohaemagglutinin-stimulated lymphocytes (LCM). The total numbers of colonies in the patients' blood and marrow were normal. When patients' marrow cells were cultured over LFL, the proportion of colonies that were eosinophilic was greater than normal (mean 21% vs 6%, P < 0.001) and this difference was accentuated when CSA was derived from LCM (mean 53% vs 15%, P < 0.001). LCM derived from normal subjects and LCM prepared from HES patients had similar effects. In the blood the total number of colonies and the proportion of eosinophilic colonies were similar in patients and controls. The overall pattern of colony formation HES differed distinctly from that observed in a patient with eosinophilic leukaemia reported previously. We conclude that the proportion of eosinophil-committed progenitor cells in the marrow of patients with HES is increased, but we have failed to demonstrate a role for the patient's own lymphocytes in augmenting eosinophil production.     

Tranexamic acid does not correct the haemostatic impairment caused by hydroxyethyl starch (200 kDa/0.5) after cardiac surgery.

We investigated the effect of intravenous tranexamic acid on hydroxyethyl starch (HES)-induced clot strength impairment after cardiac surgery. Patients were randomized to receive either 1 g tranexamic acid or the same volume of 0.9% saline after administration of 15 ml/kg of 6% HES (molecular weight, 200 kDa; degree of substitution, 0.5) in the immediate postoperative period. Modified thromboelastometry (ROTEM) using different activators [intrinsic ROTEM (InTEM), extrinsic ROTEM (ExTEM), fibrinogen ROTEM (FibTEM)] was carried out to evaluate clot formation and lysis. The clot formation time was prolonged, and the maximum clot firmness (MCF) and shear elastic modulus [G = 5000 x MCF / (100-MCF), dynes/cm(2)] decreased (all activators of ROTEM) after completion of HES (P < 0.001, two-factor analysis of variance). These abnormalities in blood coagulation persisted despite tranexamic acid. Maximal lysis (FibTEM), indicative of fibrinolytic activity, was increased after HES but no effect of tranexamic acid was observed. The cumulative chest tube drainage until the first postoperative morning was not different between the groups (1008 +/- 251 and 1081 +/- 654 ml, P = 0.698, respectively). We conclude that after cardiopulmonary bypass, HES-induced impairment in clot formation and strength, or increased fibrinolytic capacity, is not reversed by the administration of tranexamic acid.     

Temporal evolution of urate crystal deposition over articular cartilage after successful urate-lowering therapy in patients with gout: An ultrasonographic perspective

Objective: To detect evolution of ultrasonographic signs of deposition of monosodium urate crystals (MSUC) in gouty joints by serial ultrasonography after initiation of urate-lowering therapy (ULT).

Methods: Adult gout patients were examined by serial ultrasonography after initiation of ULT with target serum uric acid (SUA) Results: Thirty-eight male patients with gout with mean age of 50?±?11?years, median disease duration of 48 months and baseline mean SUA level of 8.8?±?1.5?mg/dL were recruited. Ultrasonographic evidence of MSUC deposition was detected in 89.74% of first metatarsophalangeal (MTP) joints and 27.63% of knee joints. Double contour sign (DCS), tophi, and hyperechoic spots (HES) were detected in 77.63%, 43.42%, and 19.74% of first MTPs, respectively. SUA level normalizes and plateaus after fourth month of follow-up. DCS thickness reduced significantly throughout the follow-up period. Overall, 86.25% DCS and 100% HES disappeared with median time of 6 months and 5.7 months, respectively. SUA normalization was the only significant predictor of DCS disappearance.

Conclusions: Serial ultrasonographic determination of DCS, tophi, or HES during hypouricemic therapy is a noninvasive, effective method to detect the lowering of burden of urate load in gouty joints.     

Optimal injection solution for endoscopic submucosal dissection: A randomized controlled trial of Western solutions in a porcine model

Background and Aim

When carrying out endoscopic submucosal dissection (ESD), procedural safety increases with greater tissue elevation and efficiency increases with longer‐lasting submucosal cushion. Fluids specifically developed for ESD in Asia are not commercially available in the West, leaving endoscopists to use a variety of injectable fluids off‐label. To determine the optimal fluid available in the West, we compared commonly used fluids for Western ESD.

Methods

All phases were carried out in an ex vivo porcine stomach model. Phase 1 compared tissue elevation and duration of submucosal cushions produced by various standard volumes of various injectable solutions used for ESD. The two best‐performing solutions used off‐label were tested head‐to‐head in ESD in Phase 2. Phase 3 compared the best solution from Phase 2 to Eleview^®, currently the only submucosal injection fluid approved in the USA. In Phases 2 and 3, five ESD were carried out with each solution. The solutions were randomized and the endoscopist blinded to the solution.

Results

The best‐performing solutions in Phase 1 were 0.4% hyaluronic acid, 6% hydroxyethyl starch (HES), and Eleview^®. Phase 2 compared 6% HES and hydroxypropyl methylcellulose (HPMC), showing that ESD with 6% HES was easier (P = 0.007), faster (P = 0.041) and required less injection volume (P = 0.003). In Phase 3, resection speed, ease of ESD and total volume per area resected were comparable between 6% HES and Eleview^®.

Conclusions

Of the submucosal injection fluids currently available in the West, Eleview^® and 6% HES are the best‐performing solutions for ESD in a porcine model.     

A randomized prospective analysis of alteration of hemostatic function in patients receiving tranexamic acid and hydroxyethyl starch (130/0.4) undergoing off pump coronary artery bypass surgery

Postoperative hemorrhagic complications is still one of the major problems in cardiac surgeries. It may be caused by surgical issues, coagulopathy caused by the side effects of the intravenous fluids administered to produce plasma volume expansion such as hydroxyl ethyl starch (HES). In order to thwart this hemorrhagic issue, few agents are available. Fibrinolytic inhibitors like tranexamic acid (TA) may be effective modes to promote blood conservation; but the possible complications of thrombosis of coronary artery graft, precludes their generous use in coronary artery bypass graft surgery. The issue is a balance between agents that promote coagulation and those which oppose it. Therefore, in this study we have assessed the effects of concomitant use of HES and TA. Thromboelastogram (TEG) was used to assess the effect of the combination of HES and TA. With ethical committee approval and patient's consent, 100 consecutive patients were recruited for the study. Surgical and anesthetic techniques were standardized. Patients fulfilling our inclusion criteria were randomly allocated into 4 groups of 25 each. The patients in group A received 20 ml/kg of HES (130/0.4), 10 mg/kg of T.A over 30 minutes followed by infusion of 1 mg/kg/hr over the next 12 hrs. The patients in group B received Ringer's lactate + TA at same dose. The patients in the Group C received 20 ml/kg of HES. Group D patients received RL. Fluid therapy was goal directed. Total blood loss was assessed. Reaction time (r), α angle, maximum amplitude (MA) values of TEG were assessed at baseline, 12, 36 hrs. The possible perioperative myocardial infraction (MI) was assessed by electrocardiogram (ECG) and troponin T values at the baseline, postoperative day 1. Duration on ventilator, length of stay (LOS) in the intensive care unit (ICU) were also assessed. The demographical profile was similar among the groups. Use of HES increased blood loss significantly (P < 0.05). Concomitant use of TA reduced blood loss when used along with HES. r value was prolonged at 12 hours in all the groups and α angle was reduced at 12 hours in all the groups, where as MA value was reduced at 12 th hour in the HES group compared to the baseline and increased in TA + HES group. These findings were statistically significant. No significant change in Troponin T values/ECG, duration of ventilation and LOS ICU was observed. No adverse events was noticed in any of the four groups. HES (130/0.4) used at a dose of 20 ml/kg seems to produce coagulopathy causing increased blood loss perioperatively. Hemodilution produced by fluid therapy seems to produce Coagulopathy as observed by TEG parameters. Concomitant use of TA with HES appears to reverse these changes without causing any adverse effects in patients undergoing OPCAB surgery.     

HES1 and HES4 have non-redundant roles downstream of Notch during early human T-cell development

In both mouse and human, Notch1 activation is the main initial driver to induce T-cell development in hematopoietic progenitor cells. The initiation of this developmental process coincides with Notch1-dependent repression of differentiation towards other hematopoietic lineages. Although well described in mice, the role of the individual Notch1 target genes during these hematopoietic developmental choices is still unclear in human, particularly for HES4 since no orthologous gene is present in the mouse. Here, we investigated the functional capacity of the Notch1 target genes HES1 and HES4 to modulate human Notch1-dependent hematopoietic lineage decisions and their requirement during early T-cell development. We show that both genes are upregulated in a Notch-dependent manner during early T-cell development and that HES1 acts as a repressor of differentiation by maintaining a quiescent stem cell signature in CD34⁺ hematopoietic progenitor cells. While HES4 can also inhibit natural killer and myeloid cell development like HES1, it acts differently on the T- versus B-cell lineage choice. Surprisingly, HES4 is incapable of repressing B-cell development, the most sensitive hematopoietic lineage with respect to Notch-mediated repression. In contrast to HES1, HES4 promotes initiation of early T-cell development, but ectopic expression of HES4, or HES1 and HES4 combined, is insufficient to induce T-lineage differentiation. Importantly, knockdown of HES1 or HES4 significantly reduces human T-cell development. Overall, we show that the Notch1 target genes HES1 and HES4 have non-redundant roles during early human T-cell development which may relate to differences in mediating Notch-dependent human hematopoietic lineage decisions.     

Comparison of administrative data with the Association of Coloproctology of Great Britain and Ireland (ACPGBI) colorectal cancer database

Background This study compared case volume and operative mortality from surgery for colorectal cancer in England derived from Hospital Episode Statistics (HES) with the Association of Coloproctology of Great Britain and Ireland (ACPGBI) colorectal cancer database. Materials and methods Data extracted from HES records for 2001–2002 for patients undergoing one of seven procedures for colorectal cancer were compared with those from the ACPGBI database. The primary endpoint was a 30-day post-operative mortality. Results 16,346 patients from HES were compared with 7,635 from the ACPGBI database. For trusts with patients in both databases, HES reported 12% more procedures than ACPGBI (7,516 vs 6,617). Records of anterior resection revealed reasonable agreement between HES and the ACPGBI databases (difference, 2%). By trust, the overall correlation between the reported procedures was 0.660. Reported crude mortality was inconsistent between the databases, with mortality from abdominoperineal excision of rectum showing the poorest correlation (r = 0.253). Conclusions Overall, agreement between reported caseload and mortality was reasonable at a national, but not hospital, level. Investigation of differences between the two databases at unit level may help to detect under reporting of cases. The combination of data from both sources could be used to develop an enhanced system for monitoring outcomes from colorectal surgery in England. On behalf of the Dr Foster Unit, Imperial College London and The Association of Coloproctology of Great Britain and Ireland.     

Procedural and short-term safety of bronchial thermoplasty in clinical practice: evidence from a national registry and Hospital Episode Statistics

Objective: Bronchial thermoplasty (BT) is a novel treatment for severe asthma. Its mode of action and ideal target patient group remain poorly defined, though clinical trials provided some evidence on efficacy and safety. This study presents procedural and short-term safety evidence from routine UK clinical practice. Methods: Patient characteristics and safety outcomes (procedural complications, 30-day readmission and accident and emergency (A&E) attendance, length of stay) were assessed using two independent data sources, the British Thoracic Society UK Difficult Asthma Registry (DAR) and Hospital Episodes Statistics (HES) database. A matched cohort (with records in both) was used to estimate safety outcome event rates and compare them with clinical trials. Results: Between June 2011 and January 2015, 215 procedure records (83 patients; 68 treated in England) were available from DAR and 203 (85 patients) from HES. 152 procedures matched (59 patients; 6 centres), and of these, 11.2% reported a procedural complication, 11.8% resulted in emergency respiratory readmission, 0.7% in respiratory A&E attendance within 30 days (20.4% had at least one event) and 46.1% involved a post-procedure stay. Compared with published clinical trials which found lower hospitalisation rates, BT patients in routine clinical practice were, on average, older, had worse baseline lung function and asthma quality of life. Conclusions: A higher proportion of patients experienced adverse events compared with clinical trials. The greater severity of disease amongst patients treated in clinical practice may explain the observed rate of post-procedural stay and readmission. Study of long-term safety and efficacy requires continuing data collection.     

The impact of a medium molecular weight, low molar substitution hydroxyethyl starch dissolved in a physiologically balanced electrolyte solution on blood coagulation and platelet function in vitro

BACKGROUND AND OBJECTIVES: Hydroxyethyl starches (HES) may have the potential to impact negatively on haemostasis. Recent findings suggest that side-effects on haemostasis stem not only from the physicochemical differences between HES, but also from the composition of the solvent. We compared the effects of a newly developed medium molecular weight (MW) and low molar substitution (MS) HES dissolved in a physiologically balanced electrolyte solution (MW 130, MS 0.42; B-HES) with a commercially available non-balanced HES (MW 130, MS 0.4; NB-HES), and with Ringer's lactate (RL) solution in vitro. MATERIALS AND METHODS: Activated partial thromboplastin time (APTT), factor VIII clotting activity (F VIII:C) and von Willebrand factor (vWF) activity were investigated in 48 healthy individuals. Platelet function as measured by turbidimetric platelet aggregometry and whole blood impedance aggregometry induced by adenosine diphosphate (ADP), collagen and thrombin receptor activating peptide (TRAP), and by ADP and TRAP-induced expression of activated platelet fibrinogen receptor glycoprotein (GP) IIb/IIIa was determined in 24 participants. Haemodilution (25% and 50%, v/v for blood coagulation analyses and 20% and 40%, v/v for platelet function studies) was performed using the two HES preparations and RL. RESULTS: APTT was significantly longer and F VIII and vWF significantly lower at 25% and 50% dilutions with NB-HES compared to B-HES and RL. At 20% and 40% dilutions, ADP and TRAP-induced expression of activated platelet surface GP IIb/IIIa was significantly increased by B-HES compared to NB-HES and RL. Percentages of platelet GP IIb/IIIa expression were also significantly greater in samples diluted with B-HES than in undiluted blood. Neither the diluent (B-HES, NB-HES and RL) nor the degree of dilution (undiluted, 20% and 40% dilution) had any significant influence on ADP, collagen or TRAP-induced turbidimetric platelet aggregation or impedance platelet aggregation. CONCLUSIONS: In contrast to a non-balanced 130 kDa, MS 0.4 HES (NB-HES), a 130 kDa, MS 0.42 HES preparation dissolved in a physiologically balanced electrolyte solution (B-HES) does not affect APTT, F VIII:C and vWF in vitro. Both types of HES do not affect platelet aggregation induced by ADP, collagen or TRAP. B-HES but not NB-HES increases the expression of activated platelet GP IIb/IIIa induced by ADP or TRAP.