Mapping internal temperatures during high-rate battery applications.

Electric vehicles demand high charge and discharge rates creating potentially dangerous temperature rises. Lithium-ion cells are sealed during their manufacture, making internal temperatures challenging to probe1. Tracking current collector expansion using X-ray diffraction (XRD) permits non-destructive internal temperature measurements2; however, cylindrical cells are known to experience complex internal strain3,4. Here, we characterize the state of charge, mechanical strain and temperature within lithium-ion 18650 cells operated at high rates (above 3C) by means of two advanced synchrotron XRD methods: first, as entire cross-sectional temperature maps during open-circuit cooling and second, single-point temperatures during charge-discharge cycling. We observed that a 20-minute discharge on an energy-optimized cell (3.5 Ah) resulted in internal temperatures above 70 °C, whereas a faster 12-minute discharge on a power-optimized cell (1.5 Ah) resulted in substantially lower temperatures (below 50 °C). However, when comparing the two cells under the same electrical current, the peak temperatures were similar, for example, a 6 A discharge resulted in 40 °C peak temperatures for both cell types. We observe that the operando temperature rise is due to heat accumulation, strongly influenced by the charging protocol, for example, constant current and/or constant voltage; mechanisms that worsen with cycling because degradation increases the cell resistance. Design mitigations for temperature-related battery issues should now be explored using this new methodology to provide opportunities for improved thermal management during high-rate electric vehicle applications.

Patient, family and carer experiences of nutritional screening: a systematic review.

BACKGROUND: Despite recommendations for nutritional risk screening of all inpatients, outpatients and care home residents, as well as work to assess clinician's experiences and the validity of tools, little attention has been paid to the experiences of patients undergoing nutritional screening. This review aims to synthesise systematically the current evidence regarding nutritional risk screening with respect to the experiences and views of patients, their families and carers. METHODS: A systematic search was performed in MEDLINE, Embase, PsychINFO, CINAHL, Web of Science and British Nursing Database (inception - July 2019); with screening terms related to malnutrition, screening tools and experience. Titles, abstracts and full-text papers were independently reviewed by two reviewers and then quality-appraised. Qualitative papers and quantitative surveys were included. A narrative review of surveys and a thematic framework synthesis of interviews were used to identify themes. RESULTS: Nine studies, including five qualitative interview papers, were included. Qualitative and quantitative study results were combined using a matrix chart to allow comparison. Surveyed participants reported processes of nutritional screening as acceptable. Three key themes emerged from qualitative data: (i) experience of nutritional screening; (ii) misunderstanding of malnutrition: of causes, role of screening and poor self-perception of risk; and (iii) barriers to and opportunities for change. CONCLUSIONS: Although the screening process is acceptable, patients' misunderstanding and poor knowledge regarding causes and consequences of malnutrition result in reduced risk perception and disbelief or disregard of nutritional screening results. Findings should inform policy and clinical practice, as well as highlight the known paucity of data regarding the effectiveness of screening on clinical outcomes.

Development of a core outcome set for trials on induction of labour: an international multistakeholder Delphi study.

OBJECTIVE: To develop a set of core outcomes to be minimally reported in trials on induction of labour. DESIGN: Two-round Delphi survey and consensus meeting. POPULATION: Four stakeholder groups: midwives, obstetricians, neonatologists, and women's representatives. METHODS: Protocol registered with COMET (Registration Number: 695). Stakeholders rated reported outcomes for importance (1-limited to 9-critical). The median rating of each outcome was calculated. The consensus criteria to include outcomes were as follows: ≥70% participants rated outcomes as critical and <15% rated outcomes as limited importance. Outcomes that did not achieve consensus were taken to round two and, if there was still no consensus, to the final consensus meeting. MAIN OUTCOME MEASURES: Outcomes in trials of induction of labour. RESULTS: Of the 159 invited participants, 54% (86/159) completed the first round, and 83% completed the second round (71/86). The core outcome set included 28 core outcomes in four domains: Short-term maternal outcomes (n = 18)-cardiorespiratory arrest, damage to internal organs, death, haemorrhage, hysterectomy, infection, intensive care admission, length of hospital stay, mode of delivery, need for more than one induction agent, oxytocin augmentation, postnatal depression, pulmonary embolus, satisfaction with care, stroke, time from induction to delivery, uterine hyperstimulation, uterine scar dehiscence/rupture; short-term offspring outcomes (n = 8)-admission to the neonatal unit, birth trauma, death, hypoxic ischaemic encephalopathy/need for therapeutic hypothermia, meconium aspiration syndrome, need for respiratory support, infection, and seizures; long-term maternal outcomes (n = 1)-operative pelvic floor repair; long-term offspring outcomes (n = 1)-disability including neurodevelopmental delay. CONCLUSION: Trials on induction of labour should include this core outcome set to standardise reporting. TWEETABLE ABSTRACT: International multistakeholder Delphi study identifies a core outcome set for trials on induction of labour.

Chronic breathlessness associated with poorer physical and mental health-related quality of life (SF-12) across all adult age groups.

Little is known about the impact of chronic breathlessness (modified Medical Research Council (mMRC) score ≥2 for most days, at least three of the last six months) on health-related quality of life (Short Form-12 (SF-12)). 3005 adults from randomly selected households were interviewed face-to-face in South Australia. mMRC ≥2 community prevalence was 2.9%. Adjusted analyses showed clinically meaningful and statistically significant decrements of physical and mental components of SF-12 (mean SF-12 summary scores in physical (-13.0 (-16.0 to -10.2)) and mental (-10.7 (-13.7 to -7.8)) components compared with people with mMRC=0) as chronic breathlessness severity increased, across five age groupings.

Implementation of the Needs Assessment Tool for patients with interstitial lung disease (NAT:ILD): facilitators and barriers.

A Needs Assessment Tool (NAT) was developed previously to help clinicians identify the supportive/palliative needs of people with interstitial lung disease (ILD) (NAT:ILD). This letter presents barriers and facilitators to clinical implementation. Data from (1) a focus group of respiratory clinicians and (2) an expert consensus group (respiratory and palliative clinicians, academics, patients, carers) were analysed using Framework Analysis. Barriers related to resources and service reconfiguration, and facilitators to clinical need, structure, objectiveness, flexibility and benefits of an 'aide-memoire'. Identified training needs included communication skills and local service knowledge. The NAT:ILD was seen as useful, necessary and practical in everyday practice.

Choosing outcome assessment tools in haemophilia care and research: a multidisciplinary perspective.

INTRODUCTION: The implementation of early long-term, regular clotting factor concentrate (CFC) replacement therapy ('prophylaxis') has made it possible to offer boys with haemophilia a near normal life. Many different regimens have reported favourable results, but the optimum treatment regimens have not been established and the cost of prophylaxis is very high. Both for optimizing treatment and reimbursement issues, there is a need to provide objective evidence of both short- and long-term results and benefits of prophylactic regimens. AIMS: This report presents a critical review of outcome measures for use in the assessment of musculoskeletal health in persons with haemophilia according to the International Classification of Functioning, Disability and Health (ICF). This framework considers structural and functional changes, activities and participation in a context of both personal and environmental factors. METHODS: Results were generated by a combination of a critical review of available literature plus expert opinion derived from a two day consensus conference between 48 health care experts from different disciplines involved in haemophilia assessment and care. Outcome tools used in haemophilia were reviewed for reliability and validity in different patient groups and for resources required. RESULTS AND CONCLUSION: Recommendations for choice of outcome tools were made according to the ICF domains, economic setting, and reason for use (clinical or research). The next step will be to identify a 'core' set of outcome measures for use in clinical care or studies evaluating treatment.

Prophylaxis vs. on-demand treatment with Nuwiq(®) (Human-cl rhFVIII) in adults with severe haemophilia A.

INTRODUCTION: Haemophilia A is treated with FVIII, either prophylactically or on demand. Prophylaxis is the gold standard in children and evidence is accumulating in adults. AIMS/METHODS: The aim of this analysis was to compare prophylaxis vs. on-demand treatment with Nuwiq(®) (Human-cl rhFVIII), a new-generation rFVIII expressed in a human cell line, in previously treated patients (PTPs) with severe haemophilia A. Data were analysed from two similarly designed, multinational, prospective, open-label studies with similar inclusion and exclusion criteria and comparable patient demographics. Human-cl rhFVIII was administered either prophylactically in a study of 32 adults or on-demand in a study of 22 patients (20 adults and two adolescents). RESULTS: Patients treated prophylactically experienced 36 bleeds compared with 997 bleeds in patients treated on-demand (mean observation periods: 180 and 335 days respectively). Based on a negative binomial regression model, annualized bleeding rate (ABR) during prophylaxis was 2.30 (95% CI: 1.54, 3.44) compared with 57.74 (95% CI: 43.36, 76.91) during on-demand treatment, which equates to a 96% lower ABR during prophylaxis. 'Excellent' or 'good' efficacy in the treatment of bleeds was achieved with Human-cl rhFVIII in 100% of 28 evaluated bleeds during the prophylaxis study and 94.5% of 985 evaluated bleeds during the on-demand study. No inhibitors, treatment-related serious adverse events or severe adverse events were recorded during prophylaxis or or-demand treatment. CONCLUSIONS: Prophylaxis with Human-cl rhFVIII reduces recurrent bleeding in adult PTPs with severe haemophilia A and adds further supportive evidence for the benefits of prophylaxis in adults.

Who experiences higher and increasing breathlessness in advanced cancer? The longitudinal EPCCS Study.

PURPOSE: Breathlessness is a major cause of suffering in advanced cancer. We aimed to determine the symptom trajectory in people with advanced cancer and to identify those at increased risk of experiencing higher or increasing breathlessness over time in advanced cancer. PATIENTS AND METHODS: This was an analysis of the multinational, prospective, longitudinal European Palliative Care Cancer Symptom (EPCCS) study. We included adults with confirmed incurable cancer enrolled in palliative care, with prospective monthly assessments for up to 6 months, withdrawal or death, whichever came first. Symptom severity (0-10 numerical rating scales) was analyzed using multivariate random coefficients regression. RESULTS: A total of 1689 patients (50 % women; mean age 65.7 ± [standard deviation; SD] 12.4 years) were included. Main diagnoses were digestive (31 %), lung (20 %), and breast (17 %) cancers. During a median follow-up of 62 (interquartile range, 0 to 133) days, 65 % were breathless at some point and 36 % of all patients reported moderate/severe breathlessness. The group mean (1.6 points; SD, 2.4) was unchanged over time, but the severity varied markedly between patients and over time. Independent predictors for worse breathlessness were COPD, lung cancer, living alone, lung metastases, anxiety, pain, depression, and lower performance status. Predictors of worsening breathlessness over time were low performance status (p = 0.039) and moderate to severe pain (p = 0.012). CONCLUSION: In the largest longitudinal clinical study to date in advanced cancer alone, breathlessness was frequent and associated with factors including respiratory disease, other concurrent unpleasant symptoms, and impaired performance status. Increase in severity over time was predicted by performance status and pain.

Prompt immune tolerance induction at inhibitor diagnosis regardless of titre may increase overall success in haemophilia A complicated by inhibitors: experience of two U.S. centres.

Current guidelines recommend delaying the start of immune tolerance induction (ITI) until the inhibitor titre is <10 Bethesda units (BU) to improve success. This study was conducted to evaluate ITI outcome relative to time to start ITI from inhibitor detection irrespective of inhibitor titre. Data were retrospectively collected from two U.S. haemophilia treatment centres (HTCs) on subjects with severe/moderate factor VIII (FVIII) deficiency with inhibitors who underwent ITI. Outcomes were defined pragmatically: success--negative inhibitor titre and ability to use FVIII concentrate for treatment/bleed prevention; partial success--inhibitor titre 1 to <5 BU with ability to use FVIII concentrate for treatment of bleeding; failure--ITI ongoing >3 years without achieving success/partial success, or ITI discontinuation. Fifty-eight subjects were included; 32 of 39 (82%) with high-responding inhibitor (HRI) achieved success, 7 failed. HRI subjects were subdivided based on ITI start time: 23/39 subjects started within 1 month of detection and 22/23 (96%) achieved success. Of these 23, 13 started ITI with an inhibitor titre ≥10 BU; all were successes. Eleven of 39 HRI subjects had an interval >6 months until ITI start; 7 (64%) achieved success. Time from inhibitor detection to ITI start may play a critical role in outcome. A titre ≥10 BU at ITI start did not influence outcome in subjects when ITI was initiated within 1 month of detection. Prompt ITI should be considered a viable therapeutic option in newly identified patients with inhibitors regardless of current inhibitor titre.

A study of prospective surveillance for inhibitors among persons with haemophilia in the United States.

Inhibitors are a rare but serious complication of treatment of patients with haemophilia. Phase III clinical trials enrol too few patients to adequately assess new product inhibitor risk. This project explores the feasibility of using a public health surveillance system to conduct national surveillance for inhibitors. Staff at 17 U.S. haemophilia treatment centres (HTC) enrolled patients with haemophilia A and B into this prospective study. HTC staff provided detailed historic data on product use and inhibitors at baseline, and postenrolment patients provided monthly detailed infusion logs. A central laboratory performed inhibitor tests on blood specimens that were collected at baseline, annually, prior to any planned product switch or when clinically indicated. The central laboratory also performed genotyping of all enrolled patients. From January 2006 through June 2012, 1163 patients were enrolled and followed up for 3329 person-years. A total of 3048 inhibitor tests were performed and 23 new factor VIII inhibitors were identified, 61% of which were not clinically apparent. Infusion logs were submitted for 113,205 exposure days. Genotyping revealed 431 distinct mutations causing haemophilia, 151 of which had not previously been reported elsewhere in the world. This study provided critical information about the practical issues that must be addressed to successfully implement national inhibitor surveillance. Centralized testing with routine monitoring and confirmation of locally identified inhibitors will provide valid and representative data with which to evaluate inhibitor incidence and prevalence, monitor trends in occurrence rates and identify potential inhibitor outbreaks associated with products.

Consequences of switching from prophylactic treatment to on-demand treatment in late teens and early adults with severe haemophilia A: the TEEN/TWEN study.

Although many people with haemophilia discontinue prophylaxis in their late teens or early adulthood, the consequences of this decision are largely not known. This 18-month, observational, case-controlled, multicentre study evaluated long-term prophylaxis and the consequences of switching from prophylaxis to on-demand treatment in late teens and young adults with severe haemophilia A. Participants with haemophilia (aged 14-29 years) on prophylaxis ≥ 60% of the time for the 5 years before study entry were enrolled into 1 of 2 prospective or 1 retrospective group. Group 1 was prophylaxis, group 2 had voluntarily discontinued prophylaxis ≤ 12 months before study entry and group 3 had voluntarily discontinued prophylaxis ≥ 13 months before study entry. Assessments included bleeding frequency (primary endpoint), Haemo-QoL-A health-related quality of life (HRQoL) scores, Gilbert score, development of target joints, Haemophilia Activities List, Godin Leisure-Time, treatment satisfaction and State-Trait Anxiety Inventory (secondary and exploratory endpoints). Descriptive statistics were provided for all variables. Thirty-eight participants (group 1, n = 22; group 2, n = 5; group 3, n = 11; median age, 19.5 years) were enrolled. The median annualized number of bleeding events was 0, 4.8 and 24 in groups 1, 2 and 3 respectively. HRQoL was lower in participants who discontinued prophylaxis vs. those who remained on prophylaxis. Changes in the remaining secondary and exploratory variables were small, but were generally worse in participants who discontinued prophylaxis. Following a switch from prophylaxis to on-demand therapy, the number of bleeding events increased and HRQoL worsened in late teens and young adults with severe haemophilia A.

Towards optimal use of antithrombotic therapy of people with cancer at the end of life: A research protocol for the development and implementation of the SERENITY shared decision support tool.

BACKGROUND: Even though antithrombotic therapy has probably little or even negative effects on the well-being of people with cancer during their last year of life, deprescribing antithrombotic therapy at the end of life is rare in practice. It is often continued until death, possibly resulting in excess bleeding, an increased disease burden and higher healthcare costs. METHODS: The SERENITY consortium comprises researchers and clinicians from eight European countries with specialties in different clinical fields, epidemiology and psychology. SERENITY will use a comprehensive approach combining a realist review, flash mob research, epidemiological studies, and qualitative interviews. The results of these studies will be used in a Delphi process to reach a consensus on the optimal design of the shared decision support tool. Next, the shared decision support tool will be tested in a randomised controlled trial. A targeted implementation and dissemination plan will be developed to enable the use of the SERENITY tool across Europe, as well as its incorporation in clinical guidelines and policies. The entire project is funded by Horizon Europe. RESULTS: SERENITY will develop an information-driven shared decision support tool that will facilitate treatment decisions regarding the appropriate use of antithrombotic therapy in people with cancer at the end of life. CONCLUSIONS: We aim to develop an intervention that guides the appropriate use of antithrombotic therapy, prevents bleeding complications, and saves healthcare costs. Hopefully, usage of the tool leads to enhanced empowerment and improved quality of life and treatment satisfaction of people with advanced cancer and their care givers.

Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia.

Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.

An MRI scale for assessment of haemophilic arthropathy from the International Prophylaxis Study Group.

Evaluation of prophylactic treatment of haemophilia requires sensitive methods. To design and test a new magnetic resonance imaging (MRI) scale for haemophilic arthropathy, two scales of a combined MRI scoring scheme were merged into a single scale which includes soft tissue and osteochondral subscores. Sixty-one joint MRI's of 46 patients with haemophilia were evaluated by four radiologists using the new and older scales. Forty-six of the joints were evaluated using two X-ray scales. For all MRI scores, interreader agreement and correlations with X-ray scores and lifetime number of haemarthroses were analysed. The interreader agreement intraclass correlation coefficient was 0.82, 0.89 and 0.88 for the soft tissue and osteochondral subscores and the total score, as evaluated according to the new MRI scale, compared to 0.80 and 0.89 as for the older scales. The total score and osteochondral subscore according to the new scale, as well as scores according to the older scales were correlated (P < 0.01) with number of haemarthroses (Spearman correlation 0.35-0.68) and with the X-ray scores (Spearman correlation 0.40-0.76), but no correlation (P > 0.05) was found between the soft tissue subscore of the new MRI scale and the X-ray scores. The new MRI scale is simpler to apply than the older and has similar reader reliability and correlation with lifetime number of haemarthroses, and by separating soft tissue and osteochondral changes it gives additional information. The new scale is useful for analyses of early and moderate stages of arthropathy, and may help to evaluate prophylactic haemophilia treatment.

Meeting unmet needs in inhibitor patients.

For patients with haemophilia, the development of inhibitors complicates treatment, and inhibitor patients may thus have a range of unmet needs. Although successful inhibitor eradication will render patients responsive to factor replacement therapy, with potentially beneficial effects on long-term outcomes, this may not always be possible. Physicians treating inhibitor patients should aim to achieve reliable control of bleeding episodes, and the prevention of joint disease should also be a priority. Patients with high-titre inhibitors require therapy with bypassing agents--recombinant activated factor VII (rFVIIa) or a plasma-derived activated prothrombin complex concentrate (pd-APCC)--for the treatment of bleeding. When treating joint haemorrhage in inhibitor patients, both aggressive treatment of intercurrent joint bleeds and prophylaxis should be considered, although evidence is needed as to whether prophylaxis with bypassing agents can significantly delay/prevent the development of osteochondral changes in patients with inhibitors. Despite physicians' best efforts, joint disease may ultimately occur in inhibitor patients, and in such instances optimizing treatment, of both early and late stages, is important. There is no single therapeutic modality for dealing with the various treatment challenges posed by inhibitor patients, but overall goals should be to improve quality of life, with the provision of cost-effective care that aims to maintain physical function.

'They've got to learn'--a qualitative study exploring the views of patients and staff regarding medical student teaching in a hospice.

UK medical school curricula incorporate training in end-of-life care as recommended by Tomorrow's Doctors. Previous research suggests that hospice staff have concerns about the burden on patients when participating in medical student teaching and may gatekeep access to patients. This qualitative study uses semistructured interviews to explore and compare the views of hospice patients and health care staff about patient involvement in medical student teaching. Fifteen patients and 14 staff members were recruited from a single UK hospice involved in teaching third year medical students. Hospice patients, who have been involved in teaching, are strongly positive about meeting medical students and staff carefully select patients based on a number of issues.

Mutagenesis and functional characterization of the RNA and protein components of the toxIN abortive infection and toxin-antitoxin locus of Erwinia.

Bacteria are constantly challenged by bacteriophage (phage) infection and have developed multiple adaptive resistance mechanisms. These mechanisms include the abortive infection systems, which promote "altruistic suicide" of an infected cell, protecting the clonal population. A cryptic plasmid of Erwinia carotovora subsp. atroseptica, pECA1039, has been shown to encode an abortive infection system. This highly effective system is active across multiple genera of gram-negative bacteria and against a spectrum of phages. Designated ToxIN, this two-component abortive infection system acts as a toxin-antitoxin module. ToxIN is the first member of a new type III class of protein-RNA toxin-antitoxin modules, of which there are multiple homologues cross-genera. We characterized in more detail the abortive infection phenotype of ToxIN using a suite of Erwinia phages and performed mutagenesis of the ToxI and ToxN components. We determined the minimal ToxI RNA sequence in the native operon that is both necessary and sufficient for abortive infection and to counteract the toxicity of ToxN. Furthermore, site-directed mutagenesis of ToxN revealed key conserved amino acids in this defining member of the new group of toxic proteins. The mechanism of phage activation of the ToxIN system was investigated and was shown to have no effect on the levels of the ToxN protein. Finally, evidence of negative autoregulation of the toxIN operon, a common feature of toxin-antitoxin systems, is presented. This work on the components of the ToxIN system suggests that there is very tight toxin regulation prior to suicide activation by incoming phage.

Canine dilated cardiomyopathy: a retrospective study of signalment, presentation and clinical findings in 369 cases.

OBJECTIVE: To review the clinical and diagnostic findings and survival of dilated cardiomyopathy from a large population of dogs in England. METHODS: A retrospective study of the case records of dogs with dilated cardiomyopathy collected between January 1993 and May 2006. RESULTS: There were 369 dogs with dilated cardiomyopathy of which all were pure-bred dogs except for four. The most commonly affected breeds were dobermanns and boxers. Over 95 per cent of dogs weighed more than 15 kg and 73 per cent were male. The median duration of signs before referral was three weeks with 65 per cent presenting in stage 3 heart failure. The most common signs were breathlessness (67 per cent) and coughing (64 per cent). The majority of dogs (89 per cent) had an arrhythmia at presentation and 74 per cent of dogs had radiographic signs of pulmonary oedema or pleural effusion. The median survival time was 19 weeks. CLINICAL SIGNIFICANCE: Dilated cardiomyopathy occurs primarily in medium to large breed pure-bred dogs, and males are more frequently affected than females. The duration of clinical signs before referral is often short and the survival times are poor. Greater awareness of affected breeds, clinical signs and diagnostic findings may help in early recognition of this disease which often has a short clinical phase.

Protein C deficiency.

Severe protein C deficiency (i.e. protein C activity <1 IU dL(-1)) is a rare autosomal recessive disorder that usually presents in the neonatal period with purpura fulminans (PF) and severe disseminated intravascular coagulation (DIC), often with concomitant venous thromboembolism (VTE). Recurrent thrombotic episodes (PF, DIC, or VTE) are common. Homozygotes and compound heterozygotes often possess a similar phenotype of severe protein C deficiency. Mild (i.e. simple heterozygous) protein C deficiency, by contrast, is often asymptomatic but may involve recurrent VTE episodes, most often triggered by clinical risk factors. The coagulopathy in protein C deficiency is caused by impaired inactivation of factors Va and VIIIa by activated protein C after the propagation phase of coagulation activation. Mutational analysis of symptomatic patients shows a wide range of genetic mutations. Management of acute thrombotic events in severe protein C deficiency typically requires replacement with protein C concentrate while maintaining therapeutic anticoagulation; protein C replacement is also used for prevention of these complications around surgery. Long-term management in severe protein C deficiency involves anticoagulation with or without a protein C replacement regimen. Although many patients with severe protein C deficiency are born with evidence of in utero thrombosis and experience multiple further events, intensive treatment and monitoring can enable these individuals to thrive. Further research is needed to better delineate optimal preventive and therapeutic strategies.