Venous thromboembolism risk following temporary immobilisation after injury: evaluation of the Aberdeen VTE risk tool.

BACKGROUND: Temporary lower limb immobilisation following injury is a risk factor for symptomatic venous thromboembolism (VTE). Pharmacological thromboprophylaxis can mitigate this risk but it is unclear which patients benefit from this intervention. The Aberdeen VTE risk tool was developed to tailor thromboprophylaxis decisions in these patients and this evaluation aimed to describe its performance in clinical practice. Secondarily, diagnostic metrics were compared with other risk assessment methods (RAMs). METHODS: A prospective cohort service evaluation was conducted. Adult patients (≥16 years) managed with lower limb immobilisation for injury who were evaluated with the Aberdeen VTE risk tool prior to discharge from the ED were identified contemporaneously between February 2014 and December 2020. Electronic patient records were scrutinised up to 3 months after removal of immobilisation for the development of symptomatic VTE or sudden death due to pulmonary embolism (PE). Other RAMs, including the Thrombosis Risk Prediction for Patients with cast immobilisation (TRiP(cast)) and Plymouth scores, were assimilated retrospectively and diagnostic performance compared. RESULTS: Of 1763 patients (mean age 46 (SD 18) years, 51% women), 15 (0.85%, 95% CI 0.52% to 1.40%) suffered a symptomatic VTE or death due to PE. The Aberdeen VTE tool identified 1053 (59.7%) patients for thromboprophylaxis with a sensitivity of 80.0% (95% CI 54.8% to 93.0%) and specificity of 40.4% (95% CI 38.1% to 42.6%) for the primary outcome. In 1695 patients, fewer were identified as high risk by the TRiP(cast) (33.3%) and Plymouth (24.4%) scores, but with greater specificity, 67.0% and 75.6%, respectively, than dichotomous RAMs, including the Aberdeen VTE tool. CONCLUSION: Routine use of the Aberdeen VTE tool in our population resulted in an incidence of symptomatic VTE of less than 1%. Ordinal RAMs, such as the TRiP(cast) score, may more accurately reflect VTE risk and permit more individually tailored thromboprophylaxis decisions but prospective comparison is needed.

Luminal Bioavailability of Orally Administered ω-3 PUFAs in the Distal Small Intestine, and Associated Changes to the Ileal Microbiome, in Humans with a Temporary Ileostomy.

BACKGROUND: Oral administration of purified omega-3 (ω-3) PUFAs is associated with changes to the fecal microbiome. However, it is not known whether this effect is associated with increased PUFA concentrations in the gut. OBJECTIVES: We investigated the luminal bioavailability of oral ω-3 PUFAs (daily dose 1 g EPA and 1g DHA free fatty acid equivalents as triglycerides in soft-gel capsules, twice daily) and changes to the gut microbiome, in the ileum. METHODS: Ileostomy fluid (IF) and blood were obtained at baseline, after first capsule dosing (median 2 h), and at a similar time after final dosing on day 28, in 11 individuals (median age 63 y) with a temporary ileostomy. Fatty acids were measured by LC-tandem MS. The ileal microbiome was characterized by 16S rRNA PCR and Illumina sequencing. RESULTS: There was a mean 6.0 ± 9.8-fold and 6.6 ± 9.6-fold increase in ileal EPA and DHA concentrations (primary outcome), respectively, at 28 d, which was associated with increased RBC ω-3 PUFA content (P ≤ 0.05). The first oral dose did not increase the ileal ω-3 PUFA concentration except in 4 individuals, who displayed high luminal EPA and DHA concentrations, which reduced to concentrations similar to the overall study population at day 28, suggesting physiological adaptation. Bacteroides, Clostridium, and Streptococcus were abundant bacterial genera in the ileum. Ileal microbiome variability over time and between individuals was large, with no consistent change associated with acute ω-3 PUFA dosing. However, high concentrations of EPA and DHA in IF on day 28 were associated with higher abundance of Bacteroides (r2 > 0.86, P < 0.05) and reduced abundance of other genera, including Actinomyces (r2 > 0.94, P < 0.05). CONCLUSIONS: Oral administration of ω-3 PUFAs leads to increased luminal ω-3 PUFA concentrations and changes to the microbiome, in the ileum of individuals with a temporary ileostomy. This study is registered on the ISRCTN registry as ISRCTN14530452.

A randomised trial of the effect of omega-3 polyunsaturated fatty acid supplements on the human intestinal microbiota.

OBJECTIVE: Omega-3 polyunsaturated fatty acids (PUFAs) have anticolorectal cancer (CRC) activity. The intestinal microbiota has been implicated in colorectal carcinogenesis. Dietary omega-3 PUFAs alter the mouse intestinal microbiome compatible with antineoplastic activity. Therefore, we investigated the effect of omega-3 PUFA supplements on the faecal microbiome in middle-aged, healthy volunteers (n=22). DESIGN: A randomised, open-label, cross-over trial of 8 weeks' treatment with 4 g mixed eicosapentaenoic acid/docosahexaenoic acid in two formulations (soft-gel capsules and Smartfish drinks), separated by a 12-week 'washout' period. Faecal samples were collected at five time-points for microbiome analysis by 16S ribosomal RNA PCR and Illumina MiSeq sequencing. Red blood cell (RBC) fatty acid analysis was performed by liquid chromatography tandem mass spectrometry. RESULTS: Both omega-3 PUFA formulations induced similar changes in RBC fatty acid content, except that drinks were associated with a larger, and more prolonged, decrease in omega-6 PUFA arachidonic acid than the capsule intervention (p=0.02). There were no significant changes in α or ß diversity, or phyla composition, associated with omega-3 PUFA supplementation. However, a reversible increased abundance of several genera, including Bifidobacterium, Roseburia and Lactobacillus was observed with one or both omega-3 PUFA interventions. Microbiome changes did not correlate with RBC omega-3 PUFA incorporation or development of omega-3 PUFA-induced diarrhoea. There were no treatment order effects. CONCLUSION: Omega-3 PUFA supplementation induces a reversible increase in several short-chain fatty acid-producing bacteria, independently of the method of administration. There is no simple relationship between the intestinal microbiome and systemic omega-3 PUFA exposure. TRIAL REGISTRATION NUMBER: ISRCTN18662143.

Reducing the use of inappropriate coagulation testing in emergency general surgical patients.

Background and aims Indiscriminate coagulation testing in emergency general surgical patients can lead to inappropriate delay in surgery, cause unnecessary concern and is associated with significant cost. The British Committee for Standards in Haematology recommends against coagulation testing to predict peri-operative bleeding risk in unselected patients. Our aim was to assess the appropriateness of coagulation tests performed in emergency general surgical patients and evaluate the effect of a series of educational interventions on clinical practice. Methods and results Appropriate indications for performing coagulation testing included a positive bleeding history, the presence of liver disease/cholestasis, sepsis or use of anticoagulants. Initial data on 142 patients were collected over 2 weeks of receiving. Following analysis, indications for appropriate coagulation testing were highlighted and data were collected on a further 190 patients. Comparing the audit cycles, we observed a decrease in the proportion of patients who underwent routine testing (49.3% vs 32.6%; p = 0.002) and inappropriate testing (67% of tests vs 34% of tests; p < 0.001). Despite being highlighted, there was no evidence of improved documentation of bleeding histories on admission. Conclusions This observational study suggests that simple educational messages can reduce the inappropriate use of coagulation screening tests in general surgical emergencies. This seems to result from clarification of the appropriate surgical indications for coagulation testing in this group.

Defective α2 antiplasmin cross-linking and thrombus stability in a case of acquired factor XIII deficiency.

Acquired factor XIII (FXIII) deficiency is a rare and life-threatening condition that is often misdiagnosed or missed completely. A 72-year-old woman presented with symptoms of major unprovoked bleeding but routine coagulation screening tests and platelet count were normal. Low activated FXIII (FXIIIa) activity levels and abnormal urea clot stability led to diagnosis of acquired FXIII deficiency. A modified Bethesda inhibitor titre of 1.6 Bethesda units/ml indicated the presence of a FXIII inhibitor. Bleeding responded to a single dose of FXIII concentrate and immunosuppression with prednisolone induced remission. A subsequent relapse was treated with combined prednisolone and Rituximab resulting in a prolonged, ongoing remission. Here we analyse the mechanisms underlying this idiopathic case of acquired FXIII deficiency. Prospective analysis of patient plasma revealed minimal FXIIIa activity and antigen in presentation and relapse samples. Thrombi formed from these samples lysed rapidly and showed an absence of cross-linked α2 AP. Western blotting revealed the presence of FXIII-B, indicating only FXIII-A and FXIII-A2 B2 were affected. FXIII activity and antigen levels normalised on remission. Our data suggest the presence of inhibitor-induced clearance of FXIII from plasma. As a consequence, reduced thrombus stability was evident due to defective α2 AP cross-linking, thereby explaining symptoms of excessive bleeding.

Congenital sideroblastic anemia due to mutations in the mitochondrial HSP70 homologue HSPA9.

The congenital sideroblastic anemias (CSAs) are relatively uncommon diseases characterized by defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Here we demonstrate that mutations in HSPA9, a mitochondrial HSP70 homolog located in the chromosome 5q deletion syndrome 5q33 critical deletion interval and involved in mitochondrial Fe-S biogenesis, result in CSA inherited as an autosomal recessive trait. In a fraction of patients with just 1 severe loss-of-function allele, expression of the clinical phenotype is associated with a common coding single nucleotide polymorphism in trans that correlates with reduced messenger RNA expression and results in a pseudodominant pattern of inheritance.

Does a second resection provide a survival benefit in patients diagnosed with incidental T1b/T2 gallbladder cancer following cholecystectomy?

BACKGROUND: Incidental T1b/T2 gallbladder cancers are often managed with a second resection. However it is unclear whether the additional surgical risk is associated with any survival advantage. The aim of this study was to examine the outcomes of patients who underwent a second resection following a diagnosis of incidental T1b/T2 gallbladder cancer. METHODS: A retrospective analysis of patients undergoing surgical management following a diagnosis of incidental T1b/T2 gallbladder cancer between 1994 and 2014. Survival outcomes were analysed using the Kaplan-Meier method. RESULTS: Twenty two patients underwent completion surgery following diagnosis of T1b/T2 gallbladder cancer at initial cholecystectomy, 11 of which were found to have residual disease. The presence of residual disease at second surgery in T1b/T2 disease was associated with worse overall survival (residual disease: median survival 12 months, absence of residual disease: median survival not reached, p = 0.025). CONCLUSION: A significant percentage of patients with T1b/T2 disease have identifiable residual disease following second surgery. Residual disease is associated with poor survival. It is therefore important to inform patients that completion cholecystectomy is primarily performed to inform staging rather than to improve prognosis.

Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes.

Pregnancy can precipitate thrombotic thrombocytopenic purpura (TTP). We present a prospective study of TTP cases from the United Kingdom Thrombotic Thrombocytopenic Purpura (UK TTP) Registry with clinical and laboratory data from the largest cohort of pregnancy-associated TTP and describe management through pregnancy, averting fetal loss and maternal complications. Thirty-five women presented with a first TTP episode during pregnancy: 23/47 with their first congenital TTP (cTTP) episode and 12/47 with acute acquired TTP in pregnancy. TTP presented primarily in the third trimester/postpartum, but fetal loss was highest in the second trimester. Fetal loss occurred in 16/38 pregnancies before cTTP was diagnosed, but in none of the 15 subsequent managed pregnancies. Seventeen of 23 congenital cases had a missense mutation, C3178T, within exon 24 (R1060W). There were 8 novel mutations. In acquired TTP presentations, fetal loss occurred in 5/18 pregnancies and 2 terminations because of disease. We also present data on 12 women with a history of nonpregnancy-associated TTP: 18 subsequent pregnancies have been successfully managed, guided by ADAMTS13 levels. cTTP presents more frequently than acquired TTP during pregnancy and must be differentiated by ADAMTS13 analysis. Careful diagnosis, monitoring, and treatment in congenital and acquired TTP have assisted in excellent pregnancy outcomes.

Non-HLA-matched 3rd party vascular allograft in renal transplant may lead to sensitization against donor HLA.

3rd party donor vessels are often used for vascular reconstruction in organ transplantation. While current practice ensures that 3rd party vessels are blood group matched, HLA matching to the non-intended recipient is not performed. This practice potentially sensitizes the recipient and may reduce their future chance of renal transplant from a larger pool of donors. We examined our cohort of renal transplant recipients who received non-HLA-matched 3rd party vessels for the de-novo development of donor-specific HLA antibodies. Our institution's Human Tissue Authority (HTA) blood vessel registers were examined to identify stored donor vessels and their non-intended recipients. Donor vessel HLA status was cross-referenced with the recipient HLA status. Between 2004 and 2014, five patients were identified that received 3rd party non-HLA-matched vessels for vascular reconstruction during renal transplantation. Three patients (60%) subsequently developed donor-specific HLA antibodies. These data provide evidence that use of non-HLA-matched stored 3rd party vascular grafts may lead to sensitization in the recipient. Where time permits, HLA matching should be performed to avoid this allogeneic response. Laboratories monitoring DSA should be aware of any patient receiving a non-HLA-matched 3rd party vascular graft, and recipients may benefit from increased post-transplant immunological vigilance.

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.

Destination healthcare facility of shocked trauma patients in Scotland: analysis of transfusion and surgical capability of receiving hospitals.

AIMS: Haemorrhage is a leading cause of death from trauma. Management requires a combination of haemorrhage control and resuscitation which may incur significant surgical and transfusion utilisation. The aim of this study is to evaluate the resource provision of the destination hospital of Scottish trauma patients exhibiting evidence of pre-hospital shock. METHODS: Patients who sustained a traumatic injury between November 2008 and October 2010 were retrospectively identified from the Scottish Ambulance Service electronic patients record system. Patients with a systolic blood pressure less than 110 mmHg or if missing, a heart rate greater than 120 bpm, were considered in shock. The level of the destination healthcare facility was classified in terms of surgical and transfusion capability. Patients with and without shock were compared. RESULTS: There were 135,004 patients identified, 133,651 (99.0%) of whom had sustained blunt trauma, 68,411 (50.7%) were male and the median (IQR) age was 59 (46). There were 6721 (5.0%) patients with shock, with a similar age and gender distribution to non-shocked patients. Only 1332 (19.8%) of shocked patients were taken to facilities with full surgical capability, 5137 (76.4%) to hospitals with limited (general and orthopaedic surgery only) and 252 (3.7%) to hospitals with no surgical services. In terms of transfusion capability, 5556 (82.7%) shocked patients were admitted to facilities with full capability and 1165 (17.3%) to a hospital with minimal or no capability. CONCLUSIONS: The majority of Scottish trauma patients are transported to a hospital with full transfusion capability, although the majority lack surgical sub-specialty representation.

Fibrinogenolysis and fibrinolysis in vaccine-induced immune thrombocytopenia and thrombosis.

BACKGROUND: Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome associated with adenoviral vector vaccines for COVID-19. The syndrome is characterized by thrombosis, anti-platelet factor 4 (PF4) antibodies, thrombocytopenia, high D-dimer, and hypofibrinogenemia. OBJECTIVES: To investigate abnormalities in fibrinolysis that contribute to the clinical features of VITT. METHODS: Plasma samples from 18 suspected VITT cases were tested for anti-PF4 by ELISA and characterized as meeting criteria for VITT (11/18) or deemed unlikely (7/18; non-VITT). Antigen levels of PAI-1, factor XIII (FXIII), plasmin-α2antiplasmin (PAP), and inflammatory markers were quantified. Plasmin generation was quantified by chromogenic substrate. Western blotting was performed with antibodies to fibrinogen, FXIII-A, and plasminogen. RESULTS: VITT patients 10/11 had scores indicative of overt disseminated intravascular coagulation, while 0/7 non-VITT patients met the criteria. VITT patients had significantly higher levels of inflammatory markers, IL-1ß, IL-6, IL-8, TNFα, and C-reactive protein. In VITT patients, both fibrinogen and FXIII levels were significantly lower, while PAP and tPA-mediated plasmin generation were higher compared to non-VITT patients. Evidence of fibrinogenolysis was observed in 9/11 VITT patients but not in non-VITT patients or healthy controls. Fibrinogen degradation products were apparent, with obvious cleavage of the fibrinogen α-chain. PAP complex was evident in those VITT patients with fibrinogenolysis, but not in non-VITT patients or healthy donors. CONCLUSION: VITT patients show evidence of overt disseminated intravascular coagulation and fibrinogenolysis, mediated by dysregulated plasmin generation, as evidenced by increased PAP and plasmin generation. These observations are consistent with the clinical presentation of both thrombosis and bleeding in VITT.

Spinal cord compression secondary to extramedullary haematopoiesis in transformed polycythaemia rubra vera.

Polycythaemia vera (PV) is a clonal proliferative disorder of the bone marrow characterised by autonomous haematopoiesis, which results in a panmyelosis in the peripheral blood. It is typically characterised by an acquired mutation in JAK-2 V617F. Progression to myelofibrosis (MF), characterised by worsening cytopenias and the development of constitutional symptoms, is seen in up to 10% of cases. Extramedullary haematopoiesis (EMH) in the spleen is a common finding in myelofibrotic transformation, but elsewhere in the body it is extremely unusual. We report the case of a 69-year-old male whose PV progressed to secondary MF and who presented with compression of the thoracic spinal cord directly as a result of EMH. Cytogenetic and molecular findings in the bone marrow were in keeping with evolving myeloid disease. He was managed by surgical laminectomy with an excellent outcome. Extramedullary haematopoiesis may be seen in both PV and on transformation to MF. This very rare complication should be borne in mind when managing patients with myeloproliferative disorders.