Risks of major bleeding and venous thromboembolism in patients undergoing total hip or total knee arthroplasty using therapeutic dosages of DOACs.

About 1.5% of patients undergoing total hip (THA) or total knee arthroplasty (TKA) still develop postoperative venous thromboembolism (VTE), indicating that the current thromboprophylaxis strategy is not optimal. To evaluate the feasibility of therapeutic dosages of direct oral anticoagulants (DOACs) as thromboprophylaxis for high VTE risk patients, we determined the risks of major bleeding and VTE in patients who underwent THA/TKA and were treated with DOACs in therapeutic dosages for atrial fibrillation (AF). We conducted a registry-based cohort study from 2010 to 2018 in Denmark and included AF patients on therapeutic DOACs dose who underwent THA/TKA. AF patients were utilized as proxy since they have a life-long indication for therapeutic anticoagulant medication. The 49-days cumulative incidence (with death as competing risk) of major bleeding was assessed. The same was done for VTE at 49- and 90-days. 1,354 THA and TKA procedures were included. The 49-days cumulative incidence of major bleeding was 1.40% (95%Confidence Interval[CI] 0.88-2.14%). Most bleeding events occurred at the surgical site. The cumulative incidence of VTE at 49-days was 0.59% (95%CI 0.28-1.13%) and 0.74% (95%CI 0.38-1.32%) at 90-days. The incidence of major bleeding in THA/TKA patients on DOACs in therapeutic dosages was in line with previously reported incidences among THA/TKA patients on thromboprophylaxis dosages, while the incidence of VTE was relatively low. These data provide a solid basis for the design of randomized controlled trials to establish the safety and efficacy of therapeutic dosages of DOACs to prevent VTE in high-risk patients.

Venous Thromboembolism Prophylaxis in Foot and Ankle Surgery: A Worldwide Survey.

Current recommendations on thromboprophylaxis for foot and ankle (FA) surgery are often inconsistent and generally based on weak evidence. The aim of this survey study was to evaluate the current practice among orthopedic surgeons regarding venous thromboembolism (VTE) prophylaxis following FA surgery. From February 2019 to March 2020, an online questionnaire was sent by e-mail to orthopedic societies across the world. The questionnaire was hosted by the International Society of Thrombosis and Haemostais RedCAP platform. Topics of interest were VTE rates following FA surgery, duration and type of thromboprophylaxis, bleeding complications, VTE risk factors for prophylaxis and use of risk assessment. A total of 693 FA orthopedic surgeons from all continents completed the survey of whom 392 (57%) performed more than 200 FA procedures per year. A total of 669/693 (97%) respondents stated that thromboprophylaxis is necessary in FA surgeries. When thromboprophylaxis was prescribed, half of surgeons prescribed it for the duration of immobilization. Acetylsalicylic acid, low molecular weight heparin and direct-oral anticoagulants were, in this order, the preferred choice. Acetylsalicylic acid and low molecular weight heparin were predominantly prescribed in North America and Europe, respectively. Previous deep vein thrombosis, immobility, obesity and inherited thrombophilia were considered the main risk factors indicative of thromboprophylaxis use. In this survey, most surgeons agree that thromboprophylaxis is indicated for FA surgery, but the prescription, type and duration of prophylaxis differs greatly with a large intercontinental discrepancy. These survey results could be a foundation for developing uniform guidelines to optimize thromboprophylactic strategies in FA procedures around the world.

Enhanced in vivo and ex vivo thrombin generation after lower-leg trauma, but not after knee arthroscopy.

BACKGROUND: There is room for improvement of prevention of venous thromboembolism (VTE) after lower-leg cast application or knee arthroscopy. Information about the mechanism of clot formation in these patients may be useful to identify new prophylaxis targets. We aimed to study the effect of 1) lower-leg injury and 2) knee arthroscopy on thrombin generation. METHODS: A cross-sectional study was conducted using plasma samples of POT-(K)CAST trials to measure ex vivo thrombin generation (Calibrated Automated Thrombography [CAT]) and plasma levels of prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin (TAT), fibrinopeptide A (FPA). Plasma was obtained shortly after lower-leg trauma or before and after (< 4 h) knee arthroscopy. Participants were randomly selected from those who did not develop VTE. For aim 1, samples of 88 patients with lower-leg injury were compared with 89 control samples (i.e., preoperative samples of arthroscopy patients). Linear regression was used to obtain mean differences (or ratios if ln-retransformed because of skewedness) adjusted for age, sex, body mass index, comorbidities. For aim 2, pre- and postoperative samples of 85 arthroscopy patients were compared, for which mean changes were obtained. RESULTS: In patients with lower-leg injury (aim 1), endogenous thrombin potential, thrombin peak, velocity index, FPA and TAT were increased as compared with controls. In arthroscopy patients (aim 2), pre- and postoperative levels were similar for all parameters. CONCLUSION: Lower-leg trauma increases thrombin generation both ex vivo and in vivo, in contrast to knee arthroscopy. This may imply that the pathogenesis of VTE is different in both situations.

Prevention of hip fractures in older adults residing in long-term care facilities with a hip airbag: a retrospective pilot study.

BACKGROUND: Hip and pelvic fractures do commonly occur among older adults. This pilot study aimed to evaluate the effect of introduction of the WOLK hip airbag on the incidence of hip fractures. METHODS: A retrospective study was performed among 969 participants residing within 11 long-term care facilities for older patients, belonging to one large healthcare organization in The Netherlands. The intervention concerned application of 45 WOLK hip-airbags, distributed among selected residents of the long-term care facilities. Inclusion criteria; physically active participants with a pelvic circumference between 90-125 cm able to wear the hip airbag. Exclusion criteria; participants who continuously removed the hip airbag themselves or participants who depended on a wheelchair for mobility. Main outcome measures were the occurrence of falls and hip, pelvic and other fractures. RESULTS: The incidence of hip and pelvic fractures declined from 3.3/100 person years to 1.8/100 person years during the study for an Incidence Rate Ratio (IRR) of 0.55 (95% confidence interval (95%CI) 0.34-0.87) in the entire study population. The incidence of other fractures did not decline during the study period (IRR 0.72;95%CI 0.37-1.40). The incidence of falls declined to some extent during the study (IRR 0.88; 95%CI 0.83-0.93). CONCLUSIONS: After introduction of the WOLK hip airbag a reduction of the incidence of hip and pelvic fractures by almost half was observed in older patients residing in long-term care facilities, even though only 45 hip airbags were distributed among the 969 residents. As selection bias cannot be ruled out in this study, the results of this pilot study warrant replication by a future clinical trial to determine true effectiveness of this intervention.

Effect of type 1 diabetes and type 2 diabetes on the risk of venous thromboembolism.

AIMS: Whether diabetes increases venous thromboembolism (VTE) is unclear. Any greater risk may relate to insulin resistance, but many studies did not differentiate between type 1 diabetes and type 2 diabetes for VTE risk. METHODS: Retrospective cohort study of the Royal College of General Practitioners Research and Surveillance Centre, comprising over 530 primary care practices. We determined whether type 1 diabetes and/or type 2 diabetes are independent risk factors for VTE. The index date was 1 January 2009, individuals were followed to 31 December 2018, or censoring. Cox proportional hazard regression analysis was used to investigate the risk of VTE in people with type 1 diabetes and type 2 diabetes relative to no diabetes. The primary outcome was occurrence of VTE. The model was adjusted for potential confounders for VTE. RESULTS: There were 7086 people with type 1 diabetes and 95,566 with type 2 diabetes, diagnosed before 1 January 2009. The non-diabetes group consisted of 1,407,699 people. In the unadjusted analysis, there was no increased risk of VTE with type 1 diabetes (HR 1.00, 95% CI 0.76-1.33) but there was for type 2 diabetes (HR 2.70, 95% CI 2.57-2.84). In the fully adjusted model, VTE risk was increased in type 1 diabetes (HR 1.46, 95% CI 1.11-1.92), but not with type 2 diabetes (HR 1.06, 95% CI 0.98-1.14). CONCLUSIONS: Type 1 diabetes was associated with a greater risk for VTE while type 2 diabetes was not. Further work is needed to determine the reason(s) for this.

Thromboprophylaxis after Knee Arthroscopy and Lower-Leg Casting.

BACKGROUND: The use of thromboprophylaxis to prevent clinically apparent venous thromboembolism after knee arthroscopy or casting of the lower leg is disputed. We compared the incidence of symptomatic venous thromboembolism after these procedures between patients who received anticoagulant therapy and those who received no anticoagulant therapy. METHODS: We conducted two parallel, pragmatic, multicenter, randomized, controlled, open-label trials with blinded outcome evaluation: the POT-KAST trial, which included patients undergoing knee arthroscopy, and the POT-CAST trial, which included patients treated with casting of the lower leg. Patients were assigned to receive either a prophylactic dose of low-molecular-weight heparin (for the 8 days after arthroscopy in the POT-KAST trial or during the full period of immobilization due to casting in the POT-CAST trial) or no anticoagulant therapy. The primary outcomes were the cumulative incidences of symptomatic venous thromboembolism and major bleeding within 3 months after the procedure. RESULTS: In the POT-KAST trial, 1543 patients underwent randomization, of whom 1451 were included in the intention-to-treat population. Venous thromboembolism occurred in 5 of the 731 patients (0.7%) in the treatment group and in 3 of the 720 patients (0.4%) in the control group (relative risk, 1.6; 95% confidence interval [CI], 0.4 to 6.8; absolute difference in risk, 0.3 percentage points; 95% CI, -0.6 to 1.2). Major bleeding occurred in 1 patient (0.1%) in the treatment group and in 1 (0.1%) in the control group (absolute difference in risk, 0 percentage points; 95% CI, -0.6 to 0.7). In the POT-CAST trial, 1519 patients underwent randomization, of whom 1435 were included in the intention-to-treat population. Venous thromboembolism occurred in 10 of the 719 patients (1.4%) in the treatment group and in 13 of the 716 patients (1.8%) in the control group (relative risk, 0.8; 95% CI, 0.3 to 1.7; absolute difference in risk, -0.4 percentage points; 95% CI, -1.8 to 1.0). No major bleeding events occurred. In both trials, the most common adverse event was infection. CONCLUSIONS: The results of our trials showed that prophylaxis with low-molecular-weight heparin for the 8 days after knee arthroscopy or during the full period of immobilization due to casting was not effective for the prevention of symptomatic venous thromboembolism. (Funded by the Netherlands Organization for Health Research and Development; POT-KAST and POT-CAST ClinicalTrials.gov numbers, NCT01542723 and NCT01542762 , respectively.).

Clinical outcomes of postcarotid endarterectomy hypertension.

OBJECTIVE: The objective of this study was to determine the clinical relevance of postcarotid endarterectomy hypertension (PEH) by investigating the effect of PEH on hospital length of stay (LOS) and by investigating short-term and long-term complications of PEH. In addition, risk factors for PEH were determined. METHODS: A single-center retrospective cohort study was performed. Demographic, preoperative, intraoperative, and postoperative outcomes of 192 patients undergoing carotid endarterectomy were evaluated. Outcomes were compared between patients with PEH and patients without PEH. PEH was defined as an acute systolic blood pressure (SBP) rise >170 mm Hg or persistent SBP >150 mm Hg on the ward and leading to the consultation of an internist. The overall survival and event-free survival were compared using a Kaplan-Meier analysis and a Cox regression analysis. A multivariate logistic regression analysis was performed to determine risk factors for PEH. RESULTS: PEH developed in 44 of 192 patients (25%). Preoperative hypertension (SBP >150 mm Hg) was determined to be a risk factor for PEH (odds ratio, 3.3; 95% confidence interval [CI], 1.6-6.9). Hospital LOS was prolonged in patients with PEH compared with patients without PEH (median LOS of 5 days vs 3 days, respectively; P < .001). No difference in the occurrence of ischemic neurologic events or rebleeding during hospitalization was observed (P = .58 and P = .72, respectively). Cardiovascular and ischemic neurologic events during follow-up did not occur more often in patients with PEH than in patients without PEH (P = .46). There was no difference in mortality between the PEH and non-PEH groups (hazard ratio, 1.6; 95% CI, 0.6-4.3). The same applies to the event-free survival (hazard ratio, 0.77; 95% CI, 0.4-1.7). Combined event-free survival for stroke and myocardial infarction was 92% (95% CI, 87%-97%) at 2 years for patients without PEH and 86% (95% CI, 74%-98%) at 2 years for patients with PEH (P = .25). Event-free survival for mortality was 90% (95% CI, 85%-96%) at 2 years for patients without PEH and 94% (95% CI, 86%-100%) at 2 years for patients with PEH (P = .36). CONCLUSIONS: Patients with PEH had a significant increase in hospital LOS. However, adverse short-term and long-term events did not occur more often in patients with PEH. High preoperative SBP was identified as a risk factor for PEH; no other demographic and clinical variables were associated with PEH.

Severe Infrarenal Atheroma Load in Open Aortic Aneurysm Repair Is Not a Risk Factor for Postoperative Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) after open aortic repair is subject to multiple patient- and operation-related variables. Hostile neck morphology in open aneurysm repair is thought to contribute to this AKI risk postoperatively. The aim of this study was to evaluate if large neck atheroma is a possible risk factor in the postoperative development of AKI. METHODS: Retrospectively 137 patients were evaluated for neck atheroma and AKI incidence. Atheroma load measurements were performed by 2 different techniques. Results were compared, and secondly a univariate analysis was performed for multiple additional risk factors regarding AKI occurrence. RESULTS: Significant (>30%) neck atheroma was not associated with a higher risk for developing AKI (odds ratio [OR]: 1.81; 95% confidence intervals: 0.74-4.44). Overall incidence of AKI based upon Acute Kidney Injury Network criteria was 19.7%. In univariate analysis coronary artery disease and the presence of a renal artery stenosis were both significantly associated with AKI (OR: 2.38, 3.31, respectively) as well as the use of B-blockers and angiotensin converting enzyme inhibitors (OR 3.05, 2.48, respectively). CONCLUSIONS: Cross-clamping in case of significant neck atheroma during open aortic aneurysm repair is not associated with increased risk of AKI. Defining high-risk patients based on additional risk factors must be a part of preoperative patient selection.

Determinants of Acute Kidney Injury and Renal Function Decline After Endovascular Abdominal Aortic Aneurysm Repair.

OBJECTIVE/BACKGROUND: Endovascular aneurysm repair (EVAR) may be associated with renal injury and more insight is needed into potential risk factors. The aim was to identify clinical, anatomical, and peri-procedural parameters as potential risk factors for the occurrence of acute kidney injury (AKI) and to evaluate chronic kidney disease (CKD) after EVAR. METHODS: A cohort of 212 consecutive patients who underwent elective EVAR for abdominal aortic aneurysm from January 2009 to October 2016 was included. A subgroup of 149 patients with 2 years follow-up was compared with a set of 135 non-operated aneurysm patients with smaller aneurysms (similar cardiovascular risk profile) to assess CKD. Primary outcomes were AKI (Acute Kidney Injury Network criteria) and CKD measured by estimated glomerular filtration rate (Kidney Disease Improving Global Outcomes guidelines). For AKI, candidate risk factors were identified by univariate and multivariate logistic regression analysis; for chronic renal function decline, risk factors were identified using Cox regression analysis. RESULTS: AKI occurred in 30 patients (15%). On multivariate analysis, the use of angiotensin II blocker (odds ratio [OR] 4.08, 95% confidence interval [CI] 1.38-12.07) and peri-operative complications (OR 3.12, 95% CI 1.20-8.10) were independent risk factors for AKI, whereas statin use was a protective factor (OR 0.19, 95% CI 0.07-0.52). EVAR resulted in a significant increase (23.5%) in the occurrence of CKD compared with the control group (6.7%; p <.001). On univariate and multivariate Cox regression the risk factors: aortic neck diameter (per mm increase) (hazard ratio [HR] 1.13, 95% CI 1.02-1.25), renal artery stenosis >50% (HR 2.24, 95% CI 1.05-4.79), and the occurrence of AKI (HR 2.19, 95% CI 0.99-4.85) were significant predictors of CKD. CONCLUSION: This study identified use of angiotensin II blockers and peri-operative complications as risk factors for AKI. In addition, the problem of renal function decline after EVAR is highlighted, which indicates that prolonged protective measures (e.g., in those patients at high risk) over time are needed to improve patient outcomes.

Healthcare and disease burden among refugees in long-stay refugee camps at Lesbos, Greece.

OBJECTIVES: To assess current medical problems at two Greek refugee sites at Lesbos island (Camp Moria and Caritas hotel), to explore which care is needed and to assess how the provided healthcare can be improved. DESIGN: In this dynamic cohort study all consecutive patients who visited doctors from the Boat Refugee Foundation were included. OUTCOME: Treatment Rates (TR) with 95% Confidence Intervals (95% CI) were calculated for all major health issues. Additionally, the provided health care was evaluated using the SPHERE project standards. RESULTS: During the observation period of 30 March 2016 to 15 May 2016, 2291 persons were followed for a total of 289 person years (py). The median age of patients was 23.0 (IQR 8-38) years, 30.0% was aged <18. The healthcare demand was high with 3.6 patient visits per py. Upper respiratory tract infections were most commonly diagnosed with a TR of 89.6/100py (95% CI 78.7-10.1) followed by dental problems (TR 18.0/100py, 95% CI 13.1-22.9). The rate of suicide attempts was high at TR 1.4/100py (95% CI 0.03-2.8), and many psychological problems were diagnosed, TR 19.4/100py (95% CI 14.3-24.4). Major health care threats are the lack of a vaccination program, inadequate sanitation and hygiene, and severe overcrowding. CONCLUSIONS: This study can help policy makers and Non-Governmental Organizations decide which health care is needed most in the current European refugee crisis. There is an urgent need for mental and dental healthcare. Furthermore, it is crucial that vaccination programs are initiated and "hotspot" camps should transform in camps designed for long-stay situations.

Higher incidence rates than previously known in tenosynovial giant cell tumors.

Background and purpose - Tenosynovial giant cell tumors (TGCT) are rare, benign tumors, arising in synovial lining of joints, tendon sheaths, or bursae. 2 types are distinguished: localized, either digits or extremity, and diffuse lesions. Current TGCT incidence is based on 1 single US-county study in 1980, with an incidence of 9 and 2 per million person-years in localized (including digits) and diffuse TGCT, respectively. We aim to determine nationwide and worldwide incidence rates (IR) in TGCT affecting digits, localized-extremity TGCT and diffuse-type TGCT. Material and methods - Over a 5-year period, the Dutch Pathology Registry (PALGA) identified 4,503 pathology reports on TGCT. Reports affecting digits were solely used for IR calculations. Reports affecting extremities were clinically evaluated. Dutch IRs were converted to world population IRs. Results - 2,815 (68%) digits, 933 (23%) localized-extremity and 390 (9%) diffuse-type TGCT were identified. Dutch IR in digits, localized-extremity, and diffuse-type TGCT was 34, 11 and 5 per million person-years, respectively. All 3 groups showed a female predilection and highest number of new cases in age category 40-59 years. The knee joint was most often affected: localized-extremity (46%) and diffuse-type (64%) TGCT, mostly treated with open resection: localized (65%) and diffuse (49%). Reoperation rate due to local recurrence for localized-extremity was 9%, and diffuse TGCT 23%. Interpretation - This first nationwide study and detailed analyses of IRs in TGCT estimated a worldwide IR in digits, localized-extremity and diffuse TGCT of 29, 10, and 4 per million person-years, respectively. Recurrence rate in diffuse type is 2.6 times higher, compared with localized extremity. TGCT is still considered a rare disease; however, it is more common than previously understood.

Venous Thrombosis Risk after Cast Immobilization of the Lower Extremity: Derivation and Validation of a Clinical Prediction Score, L-TRiP(cast), in Three Population-Based Case-Control Studies.

BACKGROUND: Guidelines and clinical practice vary considerably with respect to thrombosis prophylaxis during plaster cast immobilization of the lower extremity. Identifying patients at high risk for the development of venous thromboembolism (VTE) would provide a basis for considering individual thromboprophylaxis use and planning treatment studies. The aims of this study were (1) to investigate the predictive value of genetic and environmental risk factors, levels of coagulation factors, and other biomarkers for the occurrence of VTE after cast immobilization of the lower extremity and (2) to develop a clinical prediction tool for the prediction of VTE in plaster cast patients. METHODS AND FINDINGS: We used data from a large population-based case-control study (MEGA study, 4,446 cases with VTE, 6,118 controls without) designed to identify risk factors for a first VTE. Cases were recruited from six anticoagulation clinics in the Netherlands between 1999 and 2004; controls were their partners or individuals identified via random digit dialing. Identification of predictor variables to be included in the model was based on reported associations in the literature or on a relative risk (odds ratio) > 1.2 and p ≤ 0.25 in the univariate analysis of all participants. Using multivariate logistic regression, a full prediction model was created. In addition to the full model (all variables), a restricted model (minimum number of predictors with a maximum predictive value) and a clinical model (environmental risk factors only, no blood draw or assays required) were created. To determine the discriminatory power in patients with cast immobilization (n = 230), the area under the curve (AUC) was calculated by means of a receiver operating characteristic. Validation was performed in two other case-control studies of the etiology of VTE: (1) the THE-VTE study, a two-center, population-based case-control study (conducted in Leiden, the Netherlands, and Cambridge, United Kingdom) with 784 cases and 523 controls included between March 2003 and December 2008 and (2) the Milan study, a population-based case-control study with 2,117 cases and 2,088 controls selected between December 1993 and December 2010 at the Thrombosis Center, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy. The full model consisted of 32 predictors, including three genetic factors and six biomarkers. For this model, an AUC of 0.85 (95% CI 0.77-0.92) was found in individuals with plaster cast immobilization of the lower extremity. The AUC for the restricted model (containing 11 predictors, including two genetic factors and one biomarker) was 0.84 (95% CI 0.77-0.92). The clinical model (consisting of 14 environmental predictors) resulted in an AUC of 0.77 (95% CI 0.66-0.87). The clinical model was converted into a risk score, the L-TRiP(cast) score (Leiden-Thrombosis Risk Prediction for patients with cast immobilization score), which showed an AUC of 0.76 (95% CI 0.66-0.86). Validation in the THE-VTE study data resulted in an AUC of 0.77 (95% CI 0.58-0.96) for the L-TRiP(cast) score. Validation in the Milan study resulted in an AUC of 0.93 (95% CI 0.86-1.00) for the full model, an AUC of 0.92 (95% CI 0.76-0.87) for the restricted model, and an AUC of 0.96 (95% CI 0.92-0.99) for the clinical model. The L-TRiP(cast) score resulted in an AUC of 0.95 (95% CI 0.91-0.99). Major limitations of this study were that information on thromboprophylaxis was not available for patients who had plaster cast immobilization of the lower extremity and that blood was drawn 3 mo after the thrombotic event. CONCLUSIONS: These results show that information on environmental risk factors, coagulation factors, and genetic determinants in patients with plaster casts leads to high accuracy in the prediction of VTE risk. In daily practice, the clinical model may be the preferred model as its factors are most easy to determine, while the model still has good predictive performance. These results may provide guidance for thromboprophylaxis and form the basis for a management study.

Development and validation of a clinical prediction model for 90-day venous thromboembolism risk following total hip and total knee arthroplasty: a multinational study.

BACKGROUND: The risk of venous thromboembolism (VTE) following total hip arthroplasty (THA) and total knee arthroplasty (TKA) is 1.0% to 1.5%, despite uniform thromboprophylaxis. OBJECTIVES: To develop and validate a prediction model for 90-day VTE risk. METHODS: A multinational cohort study was performed. For model development, records were used from the Oxford Royal College of General Practitioners Research and Surveillance Centre linked to Hospital Episode Statistics and Office of National Statistics UK routine data. For external validation, data were used from the Danish Hip and Knee Arthroplasty Registry, the National Patient Registry, and the National Prescription Registry. Binary multivariable logistic regression techniques were used for development. RESULTS: In the UK data set, 64 032 THA/TKA procedures were performed and 1.4% developed VTE. The prediction model consisted of age, body mass index, sex, cystitis within 1 year before surgery, history of phlebitis, history of VTE, presence of varicose veins, presence of asthma, history of transient ischemic attack, history of myocardial infarction, presence of hypertension and THA or TKA. The area under the curve of the model was 0.65 (95% CI, 0.63-0.67). Furthermore, 36 169 procedures were performed in the Danish cohort, of whom 1.0% developed VTE. Here, the area under the curve was 0.64 (95% CI, 0.61-0.67). The calibration slope was 0.92 in the validation study and 1.00 in the development study. CONCLUSION: This clinical prediction model for 90-day VTE risk following THA and TKA performed well in both development and validation data. This model can be used to estimate an individual's risk for VTE following THA/TKA.

The risk of venous thromboembolism after minor surgical procedures: A population-based case-control study.

BACKGROUND: Surgery is a well-known risk factor for venous thromboembolism (VTE). However, for several minor surgical procedures, thromboprophylaxis is not advised. OBJECTIVES: These "low-risk" procedures include a wide variation of interventions for which we estimated the VTE risk to verify their "low-risk" status. PATIENTS/METHODS: We used data from a large population-based case-control study (Multiple Environment and Genetic Assessment study) into causes of VTE, and linked these to the Dutch Hospital Data Registry to identify exposure to surgical procedures. Logistic regression was used to calculate odds ratios for the 90-day and 1-year relative risks of VTE following these procedures, which were adjusted for body mass index (BMI), sex, age, comorbidities, and infection/inflammation. RESULTS: We included 4247 patients with VTE and 5538 control subjects. Median age and BMI were 48.5 years and 25.5 m2/kg, respectively. Nine unique procedures or groups of procedures were analyzed. One hundred twenty-three participants-90 cases and 33 controls-had undergone a minor procedure within 90 days of the index date, resulting in a 3.5-fold (OR, 3.5; 95% CI, 2.3-5.3) overall increased VTE risk. Furthermore, venous stripping (OR, 7.2; 95% CI, 2.4-21.2), open abdominal/inguinal hernia repair (OR, 3.7; 95% CI, 1.2-11.6), and laparoscopic cholecystectomy (OR, 3.2; 95% CI, 1.0-10.6) were associated with an increased risk. Other minor procedures were less strongly or not associated with an increased risk. In the 1-year period before the index date, all odds ratios were lower. CONCLUSION: Of the "low-risk" procedures, we found that venous stripping, open abdominal/inguinal hernia repair, and laparoscopic cholecystectomy were associated with a clearly increased risk of VTE within 90 postoperative days.

The influence of lower-leg injury and knee arthroscopy on natural anticoagulants and fibrinolysis.

BACKGROUND: Patients with lower-leg injuries and those undergoing knee arthroscopy are at increased risk of developing venous thromboembolism. The mechanism is unknown, including the influence of lower-leg injury and knee arthroscopy on natural anticoagulant factors and fibrinolysis. OBJECTIVES: To study the effect of lower-leg injury and knee arthroscopy on plasma levels of anticoagulant and fibrinolytic factors. METHODS: We applied the following 2 designs to investigate this effect: a cross-sectional study for lower-leg trauma and a before-and-after study for knee arthroscopy. Plasma samples of POT-CAST- and POT-KAST-randomized clinical trial participants (collected shortly after lower-leg trauma or before or after arthroscopy) were analyzed for clot lysis time and levels of antithrombin, tissue factor pathway inhibitor, protein C, free protein S, plasminogen, tissue plasminogen activator, plasminogen activator inhibitor 1, antiplasmin, thrombin activatable fibrinolysis inhibitor, plasmin-antiplasmin, and D-dimer. For the effect of lower-leg injury, samples of 289 patients were compared with preoperative samples of 293 arthroscopy patients, acting as controls using linear regression and adjusting for age, sex, body mass index, comorbidities, and diurnal variation. For the effect of knee arthroscopy, mean changes were calculated for 277 patients using linear mixed models adjusted for diurnal variation. Parameters other than CLT and D-dimer were measured in smaller subsets. RESULTS: In lower-leg injury patients, most parameters were stable, whereas D-dimer increased. After arthroscopy, most parameters decreased (especially clot lysis time, D-dimer, plasminogen, and anticoagulant factors), whereas tissue plasminogen activator and thrombin activatable fibrinolysis inhibitor slightly increased. CONCLUSION: In contrast to lower-leg injury, knee arthroscopy was associated with decreased natural anticoagulant factor levels. Neither lower-leg injury nor knee arthroscopy affected in vivo fibrinolysis.

Lower-leg injury and knee arthroscopy have distinct effects on coagulation.

It is unknown how lower-leg injury and knee arthroscopy, both associated with venous thromboembolism (VTE), affect coagulation. To study the effect of (1) lower-leg trauma and (2) knee arthroscopy on coagulation, plasma samples of the Prevention of Thrombosis following CAST immobilization (POT-CAST, #NCT01542762) and Prevention of Thrombosis following Knee Arthroscopy (POT-KAST, #NCT01542723) trials were used, which were collected shortly after lower-leg trauma and before/after (<4 hours) knee arthroscopy. For aim 1, 1204 lower-leg injury patients were compared with preoperative samples of 1001 controls. Mean differences/ratios (if ln-retransformed because of skewedness) were adjusted for sex, age, body mass index, comorbidity, malignancy, and oral contraceptives using linear regression. For aim 2, perioperative mean changes of 715 arthroscopy patients were calculated. Plasma levels of fibrinogen, factor (F)VIII, FIX, FXI, von Willebrand Factor (VWF), and D-dimer were measured in all individuals. Parameters of underlying mechanisms (tissue factor, interleukin-6 [IL-6], myeloperoxidase DNA, cell-free DNA) were measured in random subsets. In lower-leg injury patients, coagulation parameter levels increased, especially FVIII, VWF, and D-dimer, that is, adjusted mean differences: FVIII 26.8% (95% confidence interval [CI], 23.7-29.9), FIX 13.8% (95% CI, 11.9-15.6), FXI 5.1% (95% CI, 3.3-7.0), VWF 29.8% (95% CI, 26.0-33.6), fibrinogen 32.5 mg/dL (95% CI, 25.8-39.2), and D-dimer (mean ratio) 3.3 (95% CI, 3.1-3.6). Remaining parameters were unchanged, except for increased IL-6 levels. After arthroscopy, all parameters decreased. Lower-leg trauma is associated with increased procoagulant factor levels in contrast to knee arthroscopy. This suggests that, in both situations, different pathways are involved in development of VTE.

Effect of lower-leg trauma and knee arthroscopy on procoagulant phospholipid-dependent activity.

Background: Lower-leg injury and knee arthroscopy are both associated with venous thromboembolism (VTE). The mechanism of VTE in both situations is unknown, including the role of procoagulant microparticles. This may provide useful information for individualizing thromboprophylactic treatment in both patient groups. Objective: We aimed to study the effect of (1) lower-leg trauma and (2) knee arthroscopy on procoagulant phospholipid-dependent (PPL) activity plasma levels. Methods: POT-(K)CAST trial participants who did not develop VTE were randomly selected for the current study. Plasma was collected shortly after lower-leg trauma or before and after knee arthroscopy. For aim 1, samples of 67 patients with lower-leg injury were compared with control samples (preoperative samples of 74 patients undergoing arthroscopy). Linear regression was used to obtain mean ratios (natural logarithm retransformed data), adjusted for age, sex, body mass index, infections, and comorbidities. For aim 2, pre- and postoperative samples of 49 patients undergoing arthroscopy were compared using paired t tests. PPL activity was measured using modified activated factor X-dependent PPL clotting assay. Results: For aim 1, PPL activity levels were almost threefold higher in patients with lower-leg injury compared with controls, that is, mean ratio, 2.82 (95% confidence interval [CI], 1.98-4.03). For aim 2, postoperative PPL activity levels did not change significantly, that is, mean change, -0.72 mU/mL (95% CI, -2.03 to 0.59). Conclusion: Lower-leg trauma was associated with increased plasma levels of PPL activity, in contrast to knee arthroscopy. Lower-leg trauma triggers the release of procoagulant microparticles.

Targeted proteomics for evaluating risk of venous thrombosis following traumatic lower-leg injury or knee arthroscopy.

INTRODUCTION: Patients with lower-leg cast immobilization and patients undergoing knee arthroscopy have an increased risk of venous thrombosis (VT). Guidelines are ambiguous about thromboprophylaxis use, and individual risk factors for developing VT are often ignored. To assist in VT risk stratification and guide thromboprophylaxis use, various prediction models have been developed. These models depend largely on clinical factors and provide reasonably good C-statistics of around 70%. We explored using protein levels in blood plasma measured by multiplexed quantitative targeted proteomics to predict VT. Our aim was to assess whether a VT risk prediction model based on absolute plasma protein quantification is possible. METHODS: We used internal standards to quantify proteins in less than 10 µl plasma. We measured 270 proteins in samples from patients scheduled for knee arthroscopy or with lower-leg cast immobilization. The two prospective POT-(K)CAST trails allow complementary views of VT signature in blood, namely pre and post trauma, respectively. From approximately 3000 patients, 31 patients developed VT who were included and matched with double the number of controls. RESULTS: Top discriminating proteins between cases and controls included APOC3, APOC4, APOC2, ATRN, F13B, and F2 in knee arthroscopy patients and APOE, SERPINF2, B2M, F13B, AFM, and C1QC in patients with lower-leg cast. A logistic regression model with cross-validation resulted in C-statistics of 88.1% (95% CI: 85.7-90.6%) and 79.6% (95% CI: 77.2-82.0%) for knee arthroscopy and cast immobilization groups respectively. CONCLUSIONS: Promising C-statistics merit further exploration of the value of proteomic tests for predicting VT risk upon additional validation.