Derriford Hospital

INTRODUCTION: Next to existing terminology of the lower urinary tract, due to its increasing complexity, the terminology for pelvic floor dysfunction in women may be better updated by a female-specific approach and clinically based consensus report. METHODS: This report combines the input of members of the Standardization and Terminology Committees of two international organizations, the International Urogynecological Association (IUGA), and the International Continence Society (ICS), assisted at intervals by many external referees. Appropriate core clinical categories and a subclassification were developed to give an alphanumeric coding to each definition. An extensive process of 15 rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). RESULTS: A terminology report for female pelvic floor dysfunction, encompassing over 250 separate definitions, has been developed. It is clinically based with the six most common diagnoses defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction. Female-specific imaging (ultrasound, radiology, and MRI) has been a major addition while appropriate figures have been included to supplement and help clarify the text. Ongoing review is not only anticipated but will be required to keep the document updated and as widely acceptable as possible. CONCLUSION: A consensus-based terminology report for female pelvic floor dysfunction has been produced aimed at being a significant aid to clinical practice and a stimulus for research.

BACKGROUND: One third of patients with chronic heart failure have electrocardiographic evidence of a major intraventricular conduction delay, which may worsen left ventricular systolic dysfunction through asynchronous ventricular contraction. Uncontrolled studies suggest that multisite biventricular pacing improves hemodynamics and well-being by reducing ventricular asynchrony. We assessed the clinical efficacy and safety of this new therapy. METHODS: Sixty-seven patients with severe heart failure (New York Heart Association class III) due to chronic left ventricular systolic dysfunction, with normal sinus rhythm and a duration of the QRS interval of more than 150 msec, received transvenous atriobiventricular pacemakers (with leads in one atrium and each ventricle). This single-blind, randomized, controlled crossover study compared the responses of the patients during two periods: a three-month period of inactive pacing (ventricular inhibited pacing at a basic rate of 40 bpm) and a three-month period of active (atriobiventricular) pacing. The primary end point was the distance walked in six minutes; the secondary end points were the quality of life as measured by questionnaire, peak oxygen consumption, hospitalizations related to heart failure, the patients' treatment preference (active vs. inactive pacing), and the mortality rate. RESULTS: Nine patients were withdrawn from the study before randomization, and 10 failed to complete both study periods. Thus, 48 patients completed both phases of the study. The mean distance walked in six minutes was 22 percent greater with active pacing (399+/-100 m vs. 326+/-134 m, P<0.001), the quality-of-life score improved by 32 percent (P<0.001), peak oxygen uptake increased by 8 percent (P<0.03), hospitalizations were decreased by two thirds (P<0.05), and active pacing was preferred by 85 percent of the patients (P<0.001). CONCLUSIONS: Although it is technically complex, atriobiventricular pacing significantly improves exercise tolerance and quality of life in patients with chronic heart failure and intraventricular conduction delay.

BACKGROUND: Bruton's tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma. METHODS: In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety. RESULTS: The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months. CONCLUSIONS: Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)

The European Hernia Society (EHS) is proud to present the EHS Guidelines for the Treatment of Inguinal Hernia in Adult Patients. The Guidelines contain recommendations for the treatment of inguinal hernia from diagnosis till aftercare. They have been developed by a Working Group consisting of expert surgeons with representatives of 14 country members of the EHS. They are evidence-based and, when necessary, a consensus was reached among all members. The Guidelines have been reviewed by a Steering Committee. Before finalisation, feedback from different national hernia societies was obtained. The Appraisal of Guidelines for REsearch and Evaluation (AGREE) instrument was used by the Cochrane Association to validate the Guidelines. The Guidelines can be used to adjust local protocols, for training purposes and quality control. They will be revised in 2012 in order to keep them updated. In between revisions, it is the intention of the Working Group to provide every year, during the EHS annual congress, a short update of new high-level evidence (randomised controlled trials [RCTs] and meta-analyses). Developing guidelines leads to questions that remain to be answered by specific research. Therefore, we provide recommendations for further research that can be performed to raise the level of evidence concerning certain aspects of inguinal hernia treatment. In addition, a short summary, specifically for the general practitioner, is given. In order to increase the practical use of the Guidelines by consultants and residents, more details on the most important surgical techniques, local infiltration anaesthesia and a patient information sheet is provided. The most important challenge now will be the implementation of the Guidelines in daily surgical practice. This remains an important task for the EHS. The establishment of an EHS school for teaching inguinal hernia repair surgical techniques, including tips and tricks from experts to overcome the learning curve (especially in endoscopic repair), will be the next step. Working together on this project was a great learning experience, and it was worthwhile and fun. Cultural differences between members were easily overcome by educating each other, respecting different views and always coming back to the principles of evidence-based medicine. The members of the Working Group would like to thank the EHS board for their support and especially Ethicon for sponsoring the many meetings that were needed to finalise such an ambitious project.

PURPOSE: A classification for primary and incisional abdominal wall hernias is needed to allow comparison of publications and future studies on these hernias. It is important to know whether the populations described in different studies are comparable. METHODS: Several members of the EHS board and some invitees gathered for 2 days to discuss the development of an EHS classification for primary and incisional abdominal wall hernias. RESULTS: To distinguish primary and incisional abdominal wall hernias, a separate classification based on localisation and size as the major risk factors was proposed. Further data are needed to define the optimal size variable for classification of incisional hernias in order to distinguish subgroups with differences in outcome. CONCLUSIONS: A classification for primary abdominal wall hernias and a division into subgroups for incisional abdominal wall hernias, concerning the localisation of the hernia, was formulated.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

BACKGROUND: Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality. METHODS: In this randomised controlled trial, we recruited postmenopausal women aged 50-74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. FINDINGS: Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202,638 women: 50,640 (25·0%) to MMS, 50,639 (25·0%) to USS, and 101,359 (50·0%) to no screening. 202,546 (>99·9%) women were eligible for analysis: 50,624 (>99·9%) women in the MMS group, 50,623 (>99·9%) in the USS group, and 101,299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345,570 MMS and 327,775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0-12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0-14 of 15% (95% CI -3 to 30; p=0·10) with MMS and 11% (-7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (-20 to 31) in years 0-7 and 23% (1-46) in years 7-14, and in the USS group, of 2% (-27 to 26) in years 0-7 and 21% (-2 to 42) in years 7-14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (-2 to 40) and a reduction of 8% (-27 to 43) in years 0-7 and 28% (-3 to 49) in years 7-14 in favour of MMS. INTERPRETATION: Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7-14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening. FUNDING: Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.

The updated version of the EFSUMB guidelines on the application of non-hepatic contrast-enhanced ultrasound (CEUS) deals with the use of microbubble ultrasound contrast outside the liver in the many established and emerging applications.

BACKGROUND: Guidelines to promote the early recovery of patients undergoing major surgery recommend a restrictive intravenous-fluid strategy for abdominal surgery. However, the supporting evidence is limited, and there is concern about impaired organ perfusion. METHODS: In a pragmatic, international trial, we randomly assigned 3000 patients who had an increased risk of complications while undergoing major abdominal surgery to receive a restrictive or liberal intravenous-fluid regimen during and up to 24 hours after surgery. The primary outcome was disability-free survival at 1 year. Key secondary outcomes were acute kidney injury at 30 days, renal-replacement therapy at 90 days, and a composite of septic complications, surgical-site infection, or death. RESULTS: During and up to 24 hours after surgery, 1490 patients in the restrictive fluid group had a median intravenous-fluid intake of 3.7 liters (interquartile range, 2.9 to 4.9), as compared with 6.1 liters (interquartile range, 5.0 to 7.4) in 1493 patients in the liberal fluid group (P<0.001). The rate of disability-free survival at 1 year was 81.9% in the restrictive fluid group and 82.3% in the liberal fluid group (hazard ratio for death or disability, 1.05; 95% confidence interval, 0.88 to 1.24; P=0.61). The rate of acute kidney injury was 8.6% in the restrictive fluid group and 5.0% in the liberal fluid group (P<0.001). The rate of septic complications or death was 21.8% in the restrictive fluid group and 19.8% in the liberal fluid group (P=0.19); rates of surgical-site infection (16.5% vs. 13.6%, P=0.02) and renal-replacement therapy (0.9% vs. 0.3%, P=0.048) were higher in the restrictive fluid group, but the between-group difference was not significant after adjustment for multiple testing. CONCLUSIONS: Among patients at increased risk for complications during major abdominal surgery, a restrictive fluid regimen was not associated with a higher rate of disability-free survival than a liberal fluid regimen and was associated with a higher rate of acute kidney injury. (Funded by the Australian National Health and Medical Research Council and others; RELIEF ClinicalTrials.gov number, NCT01424150 .).

Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.

OBJECTIVE: To assess the effectiveness of metformin in improving clinical and biochemical features of polycystic ovary syndrome. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Randomised controlled trials that investigated the effect of metformin compared with either placebo or no treatment, or compared with an ovulation induction agent. SELECTION OF STUDIES: 13 trials were included for analysis, including 543 women with polycystic ovary syndrome that was defined by using biochemical or ultrasound evidence. MAIN OUTCOME MEASURE: Pregnancy and ovulation rates. Secondary outcomes of clinical and biochemical features of polycystic ovary syndrome. RESULTS: Meta-analysis showed that metformin is effective in achieving ovulation in women with polycystic ovary syndrome, with odds ratios of 3.88 (95% confidence interval 2.25 to 6.69) for metformin compared with placebo and 4.41 (2.37 to 8.22) for metformin and clomifene compared with clomifene alone. An analysis of pregnancy rates shows a significant treatment effect for metformin and clomifene (odds ratio 4.40, 1.96 to 9.85). Metformin has an effect in reducing fasting insulin concentrations, blood pressure, and low density lipoprotein cholesterol. We found no evidence of any effect on body mass index or waist:hip ratio. Metformin was associated with a higher incidence of nausea, vomiting, and other gastrointestinal disturbance. CONCLUSIONS: Metformin is an effective treatment for anovulation in women with polycystic ovary syndrome. Its choice as a first line agent seems justified, and there is some evidence of benefit on variables of the metabolic syndrome. No data are available regarding the safety of metformin in long term use in young women and only limited data on its safety in early pregnancy. It should be used as an adjuvant to general lifestyle improvements and not as a replacement for increased exercise and improved diet.

A series of 68 patients with neurosarcoidosis is reported, with particular emphasis on clinical aspects, diagnosis and treatment. A classification system based on clinical diagnostic probability is proposed, consisting of probable and definite disease, the latter being dependent on finding sarcoid granulomas on nervous system histology, which was obtained in 12 patients (18%). The role of investigations, including magnetic resonance imaging (MRI), chest radiography, Kveim skin test, Gallium 67 isotope scanning and cerebrospinal fluid (CSF) studies, is considered. Sixty-two percent of patients presented with nervous system disease, most commonly affecting the optic nerve and chiasm. Other common presentations included cranial nerve palsies, spinal cord and brainstem manifestations. Investigations yielding most diagnostic information included the Kveim test (41/48, 85% positive), raised CSF protein and/or cells (50/62, 81%) and gallium 67 scan (14/31, 45%). Eleven out of 29 patients (38%) patients showed meningeal enhancement on MRI scanning and 43% of scans demonstrated multiple white-matter lesions. Mean follow-up for the group was 4.6 years. Forty-seven patients were seen for > 18 months, and over half of these patients progressed despite corticosteroid and other immunosuppressive therapies. The benefit of a large patient database prospectively studied, with extended follow-up is discussed in order to learn more about prognosis and advance therapy in neurosarcoidosis.

BACKGROUND: Tranexamic acid reduces the risk of bleeding among patients undergoing cardiac surgery, but it is unclear whether this leads to improved outcomes. Furthermore, there are concerns that tranexamic acid may have prothrombotic and proconvulsant effects. METHODS: In a trial with a 2-by-2 factorial design, we randomly assigned patients who were scheduled to undergo coronary-artery surgery and were at risk for perioperative complications to receive aspirin or placebo and tranexamic acid or placebo. The results of the tranexamic acid comparison are reported here. The primary outcome was a composite of death and thrombotic complications (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days after surgery. RESULTS: Of the 4662 patients who were enrolled and provided consent, 4631 underwent surgery and had available outcomes data; 2311 were assigned to the tranexamic acid group and 2320 to the placebo group. A primary outcome event occurred in 386 patients (16.7%) in the tranexamic acid group and in 420 patients (18.1%) in the placebo group (relative risk, 0.92; 95% confidence interval, 0.81 to 1.05; P=0.22). The total number of units of blood products that were transfused during hospitalization was 4331 in the tranexamic acid group and 7994 in the placebo group (P<0.001). Major hemorrhage or cardiac tamponade leading to reoperation occurred in 1.4% of the patients in the tranexamic acid group and in 2.8% of the patients in the placebo group (P=0.001), and seizures occurred in 0.7% and 0.1%, respectively (P=0.002 by Fisher's exact test). CONCLUSIONS: Among patients undergoing coronary-artery surgery, tranexamic acid was associated with a lower risk of bleeding than was placebo, without a higher risk of death or thrombotic complications within 30 days after surgery. Tranexamic acid was associated with a higher risk of postoperative seizures. (Funded by the Australian National Health and Medical Research Council and others; ATACAS Australia New Zealand Clinical Trials Registry number, ACTRN12605000557639 .).

BACKGROUND: The effects of less-tight versus tight control of hypertension on pregnancy complications are unclear. METHODS: We performed an open, international, multicenter trial involving women at 14 weeks 0 days to 33 weeks 6 days of gestation who had nonproteinuric preexisting or gestational hypertension, office diastolic blood pressure of 90 to 105 mm Hg (or 85 to 105 mm Hg if the woman was taking antihypertensive medications), and a live fetus. Women were randomly assigned to less-tight control (target diastolic blood pressure, 100 mm Hg) or tight control (target diastolic blood pressure, 85 mm Hg). The composite primary outcome was pregnancy loss or high-level neonatal care for more than 48 hours during the first 28 postnatal days. The secondary outcome was serious maternal complications occurring up to 6 weeks post partum or until hospital discharge, whichever was later. RESULTS: Included in the analysis were 987 women; 74.6% had preexisting hypertension. The primary-outcome rates were similar among 493 women assigned to less-tight control and 488 women assigned to tight control (31.4% and 30.7%, respectively; adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.77 to 1.35), as were the rates of serious maternal complications (3.7% and 2.0%, respectively; adjusted odds ratio, 1.74; 95% CI, 0.79 to 3.84), despite a mean diastolic blood pressure that was higher in the less-tight-control group by 4.6 mm Hg (95% CI, 3.7 to 5.4). Severe hypertension (≥160/110 mm Hg) developed in 40.6% of the women in the less-tight-control group and 27.5% of the women in the tight-control group (P<0.001). CONCLUSIONS: We found no significant between-group differences in the risk of pregnancy loss, high-level neonatal care, or overall maternal complications, although less-tight control was associated with a significantly higher frequency of severe maternal hypertension. (Funded by the Canadian Institutes of Health Research; CHIPS Current Controlled Trials number, ISRCTN71416914; ClinicalTrials.gov number, NCT01192412.).

BACKGROUND: The survival of older patients with acute myeloid leukemia has not improved. Few clinical trials have been available for older patients who are not considered fit for an intensive chemotherapy approach. METHODS: Between December 1998 and November 2003, as part of National Cancer Research Institute Acute Myeloid Leukemia 14 Trial, 217 patients, who were deemed unfit for intensive chemotherapy were randomized to receive low-dose cytarabine (Ara-C) (20 mg twice daily for 10 days) or hydroxyurea with or without all-trans retinoic acid (ATRA). RESULTS: Low-dose ara-C produced a better remission rate (18% vs 1%; odds ratio [OR], 0.15; 95% confidence interval [95% CI], 0.06-0.37; P = .00006) and better overall survival (OR, 0.60; 95% CI, 0.44-0.81; P = .0009), which was accounted for by the achievement of complete remission (CR) (duration of CR: 80 weeks vs 10 weeks for patients with no CR). Patients who had adverse cytogenetics did not benefit. ATRA had no effect. Toxicity scores or supportive care requirements did not differ between the treatment arms. CONCLUSIONS: Older, less fit patients have a poor outcome, and few trials have been conducted in this patient group. Low-dose ara-C treatment was superior to best supportive care and hydroxyurea because it had greater success in achieving CR, and it could represent standard care against which new treatments may be compared in this patient group.

BACKGROUND: Total hip replacement is a common and highly effective operation. All hip replacements would eventually fail if in situ long enough and it is important that patients understand when this might happen. We aimed to answer the question: how long does a hip replacement last? METHODS: We did a systematic review and meta-analysis with a search of MEDLINE and Embase from the start of records to Sept 12, 2017. We included articles reporting 15-year survival of primary, conventional total hip replacement constructs in patients with osteoarthritis. We extracted survival and implant data and used all-cause construct survival as the primary outcome. We also reviewed reports of national joint replacement registries, and extracted data for a separate analysis. In the meta-analyses, we weighted each series and calculated a pooled survival estimate for each source of data. This study was registered with PROSPERO (CRD42018085642). FINDINGS: We identified 140 eligible articles reporting 150 series, and included 44 of these series (13 212 total hip placements). National joint replacement registries from Australia and Finland provided data for 92 series (215 676 total hip replacements). The 25-year pooled survival of hip replacements from case series was 77·6% (95% CI 76·0-79·2) and from joint replacement registries was 57·9% (95% CI 57·1-58·7). INTERPRETATION: Assuming that estimates from national registries are less likely to be biased, patients and surgeons can expect a hip replacement to last 25 years in around 58% of patients. FUNDING: National Institute for Health Research, National Joint Registry for England, Wales, Northern Ireland and Isle of Man, and The Royal College of Surgeons of England.

Bacterial infection is a frequent trigger of acute-on-chronic liver failure (ACLF), syndrome that could also increase the risk of infection. This investigation evaluated prevalence and characteristics of bacterial and fungal infections causing and complicating ACLF, predictors of follow-up bacterial infections and impact of bacterial infections on survival. PATIENTS: 407 patients with ACLF and 235 patients with acute decompensation (AD). RESULTS: 152 patients (37%) presented bacterial infections at ACLF diagnosis; 46%(n=117) of the remaining 255 patients with ACLF developed bacterial infections during follow-up (4 weeks). The corresponding figures in patients with AD were 25% and 18% (p<0.001). Severe infections (spontaneous bacterial peritonitis, pneumonia, severe sepsis/shock, nosocomial infections and infections caused by multiresistant organisms) were more prevalent in patients with ACLF. Patients with ACLF and bacterial infections (either at diagnosis or during follow-up) showed higher grade of systemic inflammation at diagnosis of the syndrome, worse clinical course (ACLF 2-3 at final assessment: 47% vs 26%; p<0.001) and lower 90-day probability of survival (49% vs 72.5%;p<0.001) than patients with ACLF without infection. Bacterial infections were independently associated with mortality in patients with ACLF-1 and ACLF-2. Fungal infections developed in 9 patients with ACLF (2%) and in none with AD, occurred mainly after ACLF diagnosis (78%) and had high 90-day mortality (71%). CONCLUSION: Bacterial infections are extremely frequent in ACLF. They are severe and associated with intense systemic inflammation, poor clinical course and high mortality. Patients with ACLF are highly predisposed to develop bacterial infections within a short follow-up period and could benefit from prophylactic strategies.

This study evaluates the prognostic significance of genetic abnormalities (detected at or shortly after presentation), clinical stage, lymphocyte morphology, CD38 expression, and IGVH gene status in 205 patients with chronic lymphocytic leukemia (B-CLL). Deletion of chromosome 11q23, absence of a deletion of chromosome 13q14, atypical lymphocyte morphology, and more than 30% CD38 expression are significantly associated with the presence of unmutated IGVH genes. Advanced stage, male sex, atypical morphology, more than 30% CD38 expression, trisomy 12, deletion of chromosome 11q23, loss or mutation of the p53 gene, and unmutated IGVH genes are all poor prognostic factors in a univariate analysis. However, only 98% or more homology of IGVH genes to the germline sequence, loss or mutation of the p53 gene, and clinical stage retain prognostic significance in a multivariate analysis. The median survival of patients with mutated IGVH genes, unmutated IGVH genes, and loss or mutation of the p53 gene regardless of IGVH gene status is 310, 119, and 47 months, respectively. These data should facilitate the design of new trials for the management of patients presenting with advanced disease or poor prognosis early stage disease.

PURPOSE: B cells. Single-agent epcoritamab previously demonstrated potent antitumor activity in dose escalation across B-cell non-Hodgkin lymphoma subtypes. PATIENTS AND METHODS: large B-cell lymphoma and at least two prior therapy lines (including anti-CD20 therapies) received subcutaneous epcoritamab in 28-day cycles (once weekly step-up doses in weeks 1-3 of cycle 1, then full doses once weekly through cycle 3, once every 2 weeks in cycles 4-9, and once every 4 weeks in cycle 10 and thereafter) until disease progression or unacceptable toxicity. The primary end point was overall response rate by the independent review committee. RESULTS: As of January 31, 2022, 157 patients were treated (median age, 64 years [range, 20-83]; median of three [range, 2-11] prior therapy lines; primary refractory disease: 61.1%; prior chimeric antigen receptor (CAR) T-cell exposure: 38.9%). At a median follow-up of 10.7 months, the overall response rate was 63.1% (95% CI, 55.0 to 70.6) and the complete response rate was 38.9% (95% CI, 31.2 to 46.9). The median duration of response was 12.0 months (among complete responders: not reached). Overall and complete response rates were similar across key prespecified subgroups. The most common treatment-emergent adverse events were cytokine release syndrome (49.7%; grade 1 or 2: 47.1%; grade 3: 2.5%), pyrexia (23.6%), and fatigue (22.9%). Immune effector cell-associated neurotoxicity syndrome occurred in 6.4% of patients with one fatal event. CONCLUSION: Subcutaneous epcoritamab resulted in deep and durable responses and manageable safety in highly refractory patients with large B-cell lymphoma, including those with prior CAR T-cell exposure.

• Introduction & methodology • Summary of recommendations • The scope of the guideline and concept of heritable thrombophilia as a risk factor for thrombosis • Treatment of lower limb deep vein thrombosis (DVT) and pulmonary embolus (PE) • Treatment of upper limb DVT • Treatment of cerebral vein (sinus) thrombosis (CVT) • Treatment of retinal vein thrombosis • Treatment of intra-abdominal vein thrombosis • Purpura fulminans • Case finding as a means to prevent venous thrombosis in asymptomatic relatives of patients with a history of venous thrombosis • Prevention of thrombosis associated with oestrogen-containing hormone preparations • Prevention of pregnancy-associated venous thrombosis • Pregnancy morbidity • Assisted conception and ovarian hyperstimulation syndrome • Prevention of thrombosis in hospitalised patients • Coronary, cerebral and peripheral arterial thrombosis • Perinatal stroke • Laboratory methodology and testing strategy • Audit The guideline group was selected to be representative of UK-based medical experts. The writing group met and communicated by email. The guideline was reviewed by a multidisciplinary sounding board, selected non-UK experts in thrombosis and thrombophilia, the British Committee for Standards in Haematology (BCSH) and the British Society for Haematology) (BSH and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are according to the GRADE system (Guyatt et al, 2006). As this guideline relates specifically to laboratory tests, reference is made to grading quality of evidence and strength of recommendations for diagnostic tests and strategies recognising that tests are only of value if they result in improved outcomes for patients (Schunemann et al, 2008). Strong recommendations (grade 1, ‘recommended’) are made when there is confidence that the benefits either do or do not outweigh the harm and burden and costs of treatment. Where the magnitude of benefit or not is less certain, a weaker grade 2 recommendation (‘suggested’) is made. Grade 1 recommendations can be applied uniformly to most patients whereas grade 2 recommendations require judicious application. The quality of evidence is graded as A (high quality randomised clinical trials), moderate (B) or low (C) (Guyatt et al, 2006; http://www.bcshguidelines.com). The target audience for this guideline is healthcare professionals involved in the management of patients and families with venous thrombosis or pregnancy morbidity. The summary recommendation of this guideline is that testing for heritable thrombophilias is not indicated in unselected patients presenting with venous thrombosis. Testing selected patients may give an indication of risk of recurrence following completion of anticoagulant therapy, for example those presenting with venous thrombosis at an early age (<40 years) and who are from apparent thrombosis-prone families (more than two other symptomatic family members). Analysis of the large Multiple Environmental and Genetic Assessment (MEGA) study showed that testing for inherited thrombophilia did not reduce recurrence of venous thrombosis (Coppens et al, 2008). Other selected patient groups in whom the results of testing may influence treatment are children with purpura fulminans and pregnant women at risk of venous thrombosis. The decision to test these selected patients should be based on whether or not test results are likely to influence treatment decisions. • Initiation and intensity of anticoagulant therapy following a diagnosis of acute venous thrombosis should be the same in patients with and without heritable thrombophilia (1B). • Indiscriminate testing for heritable thrombophilias in unselected patients presenting with a first episode of venous thrombosis is not indicated (1B). • Decisions regarding duration of anticoagulation (lifelong or not) in unselected patients should be made with reference to whether or not a first episode of venous thrombosis was provoked or not, other risk factors, and risk of anticoagulant therapy-related bleeding, regardless of whether a heritable thrombophilia is known (1B). • Testing for heritable thrombophilias in selected patients, such as those with a strong family history of unprovoked recurrent thrombosis, may influence decisions regarding duration of anticoagulation (C). It is not possible to give a validated recommendation as to how such patients should be selected. • Testing is not recommended in unselected patients with upper limb venous thrombosis (1B). • Testing is not recommended in patients with central venous catheter (CVC)-related thrombosis (1C). • Testing for heritable thrombophilia after a first episode of cerebral vein thrombosis (CVT) has uncertain predictive value for recurrence (C). Decisions regarding duration of anticoagulant therapy in relation to the results of testing are not evidence-based. • Testing is not indicated in patients with retinal vein occlusion (1B). • Testing for heritable thrombophilia after a first episode of intra-abdominal vein thrombosis has uncertain predictive value for recurrence (C). Decisions regarding duration of anticoagulant therapy in relation to the results of testing are not evidence-based. • Neonates and children with purpura fulminans should be tested urgently for protein C and (1B). • A of may be to 2 when levels of protein C or are not (1B). • It is that who in with are tested for protein C and after treatment is • Case finding of asymptomatic relatives with low risk thrombophilia, such as factor or is not indicated (1B). • Case finding of asymptomatic relatives with risk thrombophilia, such as of protein C or protein should only be in selected thrombosis-prone families (1B). testing is the benefits and of testing should be in the of and It is not possible to give a validated recommendation as to how such patients and families should be selected. • Case finding for or heritable thrombophilia is not indicated as these are they are not by family and the risk of unprovoked thrombosis is low • a with venous thrombosis has not tested that women an or hormone therapy Testing for heritable thrombophilia an uncertain of risk and is not recommended (1C). • a with venous thrombosis has tested and the result is that a an or Testing for heritable thrombophilia an uncertain of risk and is not recommended (1C). • a with venous thrombosis has tested and the result is that women an or testing as a test result not an risk of venous thrombosis. Testing for heritable thrombophilia may of selected women if a risk thrombophilia has in the symptomatic (C). • should be for risk of pregnancy-associated venous thrombosis in relation to clinical risk (1B). • pregnant women with a unprovoked venous thrombosis or pregnancy or thrombosis for on clinical risk and testing for heritable thrombophilia is not • women with a to a or not require or testing • women with a to a should be tested and for if a thrombophilia is • the asymptomatic pregnant with a family history of venous thrombosis, testing is not if the clinical are to result in • It is that asymptomatic pregnant women with a family history of venous thrombosis be tested if an in a was or provoked by or a risk factor The result be if the has a known • therapy should not be to pregnant women with a history of pregnancy based on testing for heritable with a or in women with a history of pregnancy are in these a benefit in women with pregnancy and heritable thrombophilia, as with women without thrombophilia, only there be a for that therapy is to pregnant women with a history of pregnancy based on testing for heritable • Testing asymptomatic women conception and those with ovarian hyperstimulation syndrome is not indicated (1B). • of hospitalised patients to patients at risk of venous thrombosis is not indicated • hospitalised patients should be for risk of venous thrombosis regardless of heritable thrombophilia based on a clinical risk (1B). The of a known heritable thrombophilia may influence the of • Testing for heritable thrombophilia is not indicated in patients with arterial thrombosis (1B). • It is that testing for heritable thrombophilia is not indicated in children with stroke for laboratory are the of the the on laboratory methodology and testing thrombophilia an inherited for venous thrombosis vein thrombosis, with or without associated pulmonary of the anticoagulant was the first inherited risk factor for venous of the protein C et al, and protein et al, with venous thrombosis. other risk only the factor et al, and the et al, to be associated with an risk of venous thrombosis & of 2 or the and thrombophilia testing in unselected patients and relatives the that there was evidence that testing clinical It is apparent that testing for heritable thrombophilia not of recurrence in unselected patients with symptomatic venous thrombosis et al, et al, and testing for inherited thrombophilia did not reduce recurrence of venous thrombosis in a large study (Coppens et al, 2008). is a low risk of thrombosis in asymptomatic relatives & and the results of thrombophilia tests are et al, The of this guideline is to recommendations to in relation to testing for heritable thrombophilia in the of clinical management of venous thrombosis and pregnancy morbidity. guideline is to heritable thrombophilias to be associated with at a risk of venous thrombosis, of protein C and protein to in the and the two factor and to as the the of the Committee for Standards in Haematology) guideline and of in randomised of treatment in relation to heritable thrombophilia A of the clinical of thrombophilia testing was in & and of the of heritable thrombophilias with the clinical of testing has not in these where the clinical of testing is testing is not as the of a test to influence or clinical used thrombophilia test results to clinical example of this is the management of women at risk of pregnancy-associated venous thrombosis. The guideline pregnancy-associated venous thrombosis risk on the of thrombophilia test results and testing was in to the the recommendations on low quality It is that randomised the of risk of pregnancy-associated venous thrombosis and is in this guideline recognising that there is only low evidence and that of clinical risk is in Criteria for thrombosis-prone families not The family history of venous thrombosis and of inherited thrombophilia is et al, 2006). a family history of venous thrombosis is not a risk factor for recurrent venous thrombosis if patients with protein C or protein are et al, 2006). The influence of family history on recurrence risk in patients with of protein C or protein is evidence that heritable thrombophilia should influence the intensity of anticoagulation with or a of in with was and recurrence or of thrombosis on treatment was than in patients for venous thrombosis & is in patients with protein C or such that most with protein C or do not there is indication that of anticoagulant treatment patients are should be in patients known to protein C or The intensity of therapy with should not be by laboratory evidence of inherited is evidence that recurrence on treatment is likely in patients with heritable thrombophilia et al, • Initiation and intensity of anticoagulant therapy following a diagnosis of acute venous thrombosis should be the same in patients with and without heritable thrombophilia (1B). that finding a heritable thrombophilia not recurrence et al, et al, of the study showed that testing for inherited thrombophilia did not reduce recurrence of venous thrombosis (Coppens et al, 2008). of the risk of recurrent venous in patients for the a risk of and for the et al, 2006; et al, The that the magnitude of the in risk was and by did not an duration of patients with of a anticoagulant protein protein the risk of recurrence is uncertain of recurrence to be in patients who are not selected from thrombosis-prone families et al, et al, et al, a of patients selected on the of age at of first venous thrombosis and a family history of venous thrombosis, of of a anticoagulant a risk of recurrence of to in patients with or a this a risk of recurrence of et al, is strategy in of patients with patients may be by clinical risk or in with tests of such as et al, 2008). the duration of anticoagulant therapy should be by a clinical of risk and benefit after an of anticoagulant therapy et al, the of patients this not or be testing for heritable • Indiscriminate testing for heritable thrombophilia in unselected patients presenting with a first episode of venous thrombosis is not indicated (1B). • Decisions regarding duration of anticoagulation (lifelong or not) in unselected patients should be made with reference to whether or not a first episode of venous thrombosis was provoked or not, other risk factors, and risk of anticoagulant therapy-related bleeding, regardless of whether a heritable thrombophilia is known (1B). • Testing for heritable thrombophilia in selected patients, such as those with a strong family history of unprovoked recurrent thrombosis, may influence decisions regarding duration of anticoagulation (C). It is not possible to give a validated recommendation as to how such patients should be selected. than of of upper limb DVT are associated with central venous et al, with and the risk et al, 2008). syndrome is less thrombophilias are in of patients without these and there is an thrombophilias and et al, The risk of recurrence is either not or in patients with heritable thrombophilias the risk of recurrence in the of thrombophilia is and of patients are after anticoagulant therapy et al, et al, 2008). study an risk of thrombosis in patients with thrombophilia the study was and is uncertain how treatment be by of a in this • Testing is not recommended in unselected patients with upper limb venous thrombosis (1B). • Testing is not recommended in patients with venous thrombosis (1C). is an thrombophilia and cerebral vein thrombosis with an and et al, 2006; et al, 2008). the risk of recurrence of is lower than to of et al, recurrence may be to of anticoagulant therapy in those patients to be at A study in children the as an risk factor for recurrence It has to test patients for heritable thrombophilia after and experts anticoagulation if there is a patients should be or or • Testing for heritable thrombophilias after a first episode of has uncertain predictive value for recurrence (C). Decisions regarding duration of anticoagulant therapy in relation to the results of testing are not evidence-based. vein occlusion is associated with and did not a with heritable thrombophilia that and be risk et al, A an of for a weaker than with lower limb DVT et al, 2008). It is uncertain to is a factor in this and the risk of recurrence is there is evidence that anticoagulant therapy is is not recommended that decisions regarding treatment are made in relation to the results of testing for heritable • Testing is not indicated in patients with retinal vein occlusion (1B). and are strong risk for intra-abdominal venous thrombosis. The is a risk factor in the of an in of & 2008). A of of vein thrombosis an of for and for et al, 2008). how the finding of a heritable thrombophilia should influence • Testing for heritable thrombophilias after a first episode of intra-abdominal vein thrombosis has uncertain predictive value for recurrence (C). Decisions regarding duration of anticoagulant therapy in relation to the results of testing are not evidence-based. Purpura fulminans is a syndrome by that in with protein C at or in the first of and in with in children and The may in children without inherited anticoagulant following with an of protein has in purpura fulminans following and is associated with a morbidity and without treatment. is for example in patients with or purpura fulminans to treatment with protein C should be patients with testing for protein C or should be as may be Neonates for protein C or may be with or may be with a of 1 and 2 and may be to as as to a in the of protein C not be by a on testing should be in for protein C or protein may when with this is and may be to of anticoagulation in the of • Neonates and children with purpura fulminans should be tested urgently for protein C and (1B). • A of may be to 2 when levels of protein C or are not (1B). • It is that who in with are tested for protein C and when treatment is It has that testing for heritable thrombophilia in patients presenting with venous thrombosis of asymptomatic family The is that this of as of by or an for at of risk as risk is by and factors, be the risk of venous thrombosis in asymptomatic family by testing unselected patients presenting with venous thrombosis et al, et al, et al, et al, in a in & The of the the risk of venous thrombosis in asymptomatic family relatives of patients was for those with for protein C for protein and for & risk to of in patients with and to reduce a of asymptomatic relatives with the the of venous thrombosis was in and in a that was not et al, a study of asymptomatic of of protein C or protein the of venous thrombosis was confidence with provoked with an of of risk et al, finding of asymptomatic relatives of patients with venous thrombosis has not to reduce the of venous thrombosis and the risk of unprovoked thrombosis in family is the on patients to for thrombophilia testing if they a or family history of venous thrombosis. The of venous thrombosis on study was in asymptomatic The risk of venous thrombosis was in with the risk in relatives of patients with of a anticoagulant or et al, a an of of asymptomatic a first episode of venous thrombosis, to in a of the unprovoked et al, The was in and in The was in with or a study of families with 1 the of venous thrombosis was in family was on et al, this study the of venous thrombosis in family in in they to or was in in there was the of unprovoked venous thrombosis was only is only than the in an unselected et al, of relatives with or thrombophilia, such as of protein C or protein has & there is evidence to the clinical of such an and the the experts that is to testing if is that clinical management be for example an or of a risk a family history a of be to test a symptomatic patient and with a to at of risk in example in in pregnancy when there is a family history of pregnancy-associated venous thrombosis, or or when there is a history of in the benefits and of testing should be in the of and risk 2008). The of this is by after testing et al, et al, et al, and an of risk et al, the of in thrombosis-prone families has not for a family history do not patients with and without thrombophilia and the decision to test for inherited thrombophilia be by the or of a family • Case finding of asymptomatic relatives with low risk thrombophilia, such as is not indicated (1B). • Case finding of asymptomatic relatives with risk thrombophilia, such as of protein C or protein should only be in selected thrombosis-prone families (1B). testing is the benefits and of testing should be in the of and It is not possible to give a validated recommendation as to how such patients and families should be selected. • Case finding for or heritable thrombophilia is not indicated as these are they are not by family and the risk of unprovoked thrombosis is low women heritable thrombophilia has in is that testing decision regarding of a or the risk of thrombosis is low and the that venous thrombosis has a with in relation to testing uncertain an is to the risk is as the is is there a indication for and in most there is only a is are associated with a lower risk of venous thrombosis et al, 2008). the in thrombophilia be in decision a for unselected women was as the most et al, A has for testing relatives of et al, 2008). the on such as women testing not a or and that of venous thrombosis are to these low risk has not in the A with a history of venous thrombosis is a to an oestrogen-containing The risk is on the of thrombosis in the a history of an who venous thrombosis as a of is not a a with unprovoked venous thrombosis, or specifically a venous thrombosis a should be a strong families with known heritable the risk of venous thrombosis can be in as as and a thrombophilia result not an risk of venous thrombosis. decisions regarding of oestrogen-containing preparations and whether thrombophilia testing is likely to be should be made with reference to clinical risk and the associated with venous thrombosis in the • a with venous thrombosis has not tested an or Testing for heritable thrombophilia an uncertain of risk and is not recommended (1C). • a with venous thrombosis has tested and the result is an or Testing for heritable thrombophilia an uncertain of risk and is not recommended (1C). • a with venous thrombosis has tested and the result is an or testing as a test result not an risk of venous thrombosis. Testing for heritable thrombophilia may of selected women if a risk thrombophilia has in the symptomatic (C). to from the of and is recommended of and Pregnancy is associated with a to risk of venous thrombosis to women of age with an risk of 1 to 2 et al, 2006). The risk of venous thrombosis, to the is in pregnancy in women with a thrombosis et al, an of of from 1 pregnancy in the the risk for pregnancy-associated venous thrombosis thrombophilia and a history of thrombosis et al, 2006). of and of not in a study of women with venous thrombosis for whom on the thrombophilia was the of recurrence was in women with and without thrombophilia, only women risk thrombophilias et al, this study women with a episode of venous thrombosis pregnant and did not in thrombosis in of did not in women was a finding to a study et al, a study of women with of protein C or protein from families from testing patients with venous thrombosis the risk of pregnancy-associated venous thrombosis was after of the et al, of women and of women venous thrombosis of of in women by venous thrombosis with of in a of thrombophilias there was an associated risk of venous thrombosis in those with thrombophilia et al, 2006). The risk was in and in women who for the or for the The risk of venous thrombosis in women with was and for protein C and protein as to not the risk of pregnancy-associated venous thrombosis in women with heritable thrombophilia with history is women with or those for the or the or who are should be as at The of women with these is women with a history of venous thrombosis the factor in whether should be is if venous thrombosis was provoked or the episode was should be and thrombophilia testing is not if is women with a first provoked the decision to test or not should be by the strength of the for example venous thrombosis associated with and not be an indication for or women with a with thrombosis the decision to test should be by whether or not the in the was unprovoked or provoked and the strength of the the in the was pregnancy or testing and finding thrombophilia should of if the symptomatic was known to the same of or protein testing in pregnancy is to the results with reference to the of pregnancy on the • should be for risk of pregnancy-associated venous thrombosis in relation to clinical risk (1B). • women with a unprovoked venous thrombosis or pregnancy or thrombosis for on clinical risk and testing for heritable thrombophilia is not • with a to a or not require or testing • with a to a should be tested and for if a thrombophilia is • the asymptomatic with a family history of venous thrombosis testing is not if the clinical are to result in • It is that asymptomatic women with a family history of venous thrombosis be tested if an in a was or provoked by or a risk factor The result be if the has a known is evidence of an heritable thrombophilia and pregnancy morbidity early and pregnancy and et al, & et al, 2006; & 2008). decisions should be based on clinical and not on the results of thrombophilia in the of the years) with a history a decision to with low should not be by the results of testing for heritable • therapy should not be to pregnant women based on tests for heritable with a treatment or in women with a history of pregnancy are in these a benefit in women with pregnancy and heritable thrombophilia, as with women without thrombophilia, only there be a for that therapy is to pregnant women with a history of pregnancy based on testing for heritable hyperstimulation is associated with an risk of venous and arterial thrombosis. the risk of venous thrombosis in these women is and to be treatment & a to that of pregnancy-associated venous thrombosis. who venous thrombosis in with ovarian hyperstimulation with upper limb or vein thrombosis for that are The of thrombophilia is not in women with hyperstimulation As the of the is low the predictive value of thrombophilia testing be low and testing should not be used to influence strategies in women ovarian • Testing asymptomatic women conception and those with ovarian hyperstimulation syndrome is not indicated (1B). for hospitalised patients should be in with a risk based on and risk for venous thrombosis. for heritable thrombophilia is not indicated a heritable thrombophilia may influence the of • of hospitalised patients to patients at risk of venous thrombosis is not indicated • hospitalised patients should be for risk of venous thrombosis regardless of heritable thrombophilia based on a clinical risk (1B). The of a known heritable thrombophilia may influence the of of an heritable thrombophilia and arterial thrombosis is to and & 2008). It is possible that heritable that result in the of & as there is an arterial and venous thrombosis risk et al, patients presenting with venous thrombosis the age of there is an risk of acute et al, 2008). the of heritable thrombophilia, as with risk factors, is not to therapy for and patients are tested after an arterial (Coppens et al, As there is and as treatment and should be in relation to risk factors, thrombophilia testing is not • Testing for heritable thrombophilia is not indicated in patients with arterial thrombosis (1B). Testing may a factor not management decisions. anticoagulant therapy is not and in children there may be a a is or the of stroke stroke in the • It is that testing for heritable thrombophilia is not indicated in children with stroke for laboratory Committee for Standards in Haematology should be used where and are a protein C not a protein C with to a in the a protein C be to this the of the result in for other as to a the of be by and the with as as the of and the example an a may not be associated with an risk of venous thrombosis. in families with a may to and et al, The of thrombophilia test results is and in are results in and et al, and may not be and are thrombosis to is diagnosis should be when there is a in the of of the heritable thrombophilias by this and levels of and and the of patients with is indicated by and the of results on the of • Testing at the of acute venous thrombosis is not indicated as the and of testing to be and the patient to be As treatment of acute venous thrombosis is not by test testing can be if • The should be to the of a in protein C and • should be used to and protein C • of protein C are less to than and are • of protein are to a protein is used in the low results should be with an of protein • an protein is to the the test of the test in factor as to the test should be the should be by a is if a test for is used • testing for of of protein C and protein is indicated and a low should be on or should not be on a • quality and in quality are • testing be by laboratory and the clinical of the results be by an who is of that may influence test results in The recommended (grade and (grade for testing or not testing can be used as to for thrombophilia It is that clinical management decisions in patients for whom thrombophilia testing was to that decisions regarding intensity and duration of anticoagulation are not made on the of the thrombophilia test anticoagulation after a first episode of venous thrombosis on the of testing and finding the in quality should be the and in these is to be and at the of to the the British Society for Haematology the for the of these of the British Committee for Standards in