Direct puncture versus contralateral femoral artery approach for catheter-directed thrombolysis of occluded infra-inguinal arterial bypass grafts.

AIM: To compare the safety, effectiveness, and clinical outcome of percutaneous direct puncture approach versus contralateral femoral native vessel approach for catheter-directed thrombolysis of occluded infra-inguinal bypass grafts. MATERIALS AND METHODS: A retrospective analysis was performed comprising a cohort of patients who underwent catheter-directed thrombolysis procedures of occluded infra-inguinal bypass grafts between January 2013 and January 2022, with a follow-up period until June 2022. This included 55 procedures via the native vessel approach and 18 procedures via the direct puncture approach. Primary outcomes were technical success and procedural safety; secondary outcomes included re-intervention rate, limb salvage, and mortality as assessed by log-rank testing and Kaplan-Meier curves. RESULTS: There were no differences between the two groups with regard to patient demographics, except for the number of previous vascular procedures (n=6.83 ± 3.07 direct approach versus n=4.96 ± 2.79 native vessel approach, p=0.025). Thrombolysis was comparably successful in both groups (n=13/18; 72% direct approach versus n=42/55; 76%, p=0.723). There were no differences in the duration of thrombolysis administration. The rate of adverse events was slightly lower in the direct approach group, but without significance (p=0.092). There were no adverse events related to the puncture site in the direct approach group. No differences were found between the time-to-event values for re-occlusion, re-intervention, amputation, or mortality respectively (p=0.662; p=0.520; p=0.816; p=0.462). CONCLUSION: The direct puncture approach seems to be a safe and efficient approach for catheter-directed thrombolysis procedures in infra-inguinal occluded bypass grafts, with clinical outcomes comparable to the native vessel approach.

Patients with Lemierre syndrome have a high risk of new thromboembolic complications, clinical sequelae and death: an analysis of 712 cases.

BACKGROUND: Lemierre syndrome is characterized by head/neck vein thrombosis and septic embolism usually complicating an acute oropharyngeal bacterial infection in adolescents and young adults. We described the course of Lemierre syndrome in the contemporary era. METHODS: In our individual-level analysis of 712 patients (2000-2017), we included cases described as Lemierre syndrome if these criteria were met: (i) primary site of bacterial infection in the head/neck; (ii) objectively confirmed local thrombotic complications or septic embolism. The study outcomes were new or recurrent venous thromboembolism or peripheral septic lesions, major bleeding, all-cause death and clinical sequelae. RESULTS: The median age was 21 (Q1-Q3: 17-33) years, and 295 (41%) were female. At diagnosis, acute thrombosis of head/neck veins was detected in 597 (84%) patients, septic embolism in 582 (82%) and both in 468 (80%). After diagnosis and during in-hospital follow-up, new venous thromboembolism occurred in 34 (5.2%, 95% CI 3.8-7.2%) patients, new peripheral septic lesions became evident in 76 (11.7%; 9.4-14.3%). The rate of either was lower in patients who received anticoagulation (OR: 0.59; 0.36-0.94), higher in those with initial intracranial involvement (OR: 2.35; 1.45-3.80). Major bleeding occurred in 19 patients (2.9%; 1.9-4.5%), and 26 died (4.0%; 2.7-5.8%). Clinical sequelae were reported in 65 (10.4%, 8.2-13.0%) individuals, often consisting of cranial nerve palsy (n = 24) and orthopaedic limitations (n = 19). CONCLUSIONS: Patients with Lemierre syndrome were characterized by a substantial risk of new thromboembolic complications and death. This risk was higher in the presence of initial intracranial involvement. One-tenth of survivors suffered major clinical sequelae.

D-dimer levels and risk of recurrence following provoked venous thromboembolism: findings from the RIETE registry.

BACKGROUND: Patients with venous thromboembolism (VTE) secondary to transient risk factors may develop VTE recurrences after discontinuing anticoagulation. Identifying at-risk patients could help to guide the duration of therapy. METHODS: We used the RIETE database to assess the prognostic value of d-dimer testing after discontinuing anticoagulation to identify patients at increased risk for recurrences. Transient risk factors were classified as major (postoperative) or minor (pregnancy, oestrogen use, immobilization or recent travel). RESULTS: In December 2018, 1655 VTE patients with transient risk factors (major 460, minor 1195) underwent d-dimer measurements after discontinuing anticoagulation. Amongst patients with major risk factors, the recurrence rate was 5.74 (95% CI: 3.19-9.57) events per 100 patient-years in those with raised d-dimer levels and 2.68 (95% CI: 1.45-4.56) in those with normal levels. Amongst patients with minor risk factors, the rates were 7.79 (95% CI: 5.71-10.4) and 3.34 (95% CI: 2.39-4.53), respectively. Patients with major risk factors and raised d-dimer levels (n = 171) had a nonsignificantly higher rate of recurrences (hazard ratio [HR]: 2.14; 95% CI: 0.96-4.79) than those with normal levels. Patients with minor risk factors and raised d-dimer levels (n = 382) had a higher rate of recurrences (HR: 2.34; 95% CI: 1.51-3.63) than those with normal levels. On multivariate analysis, raised d-dimers (HR: 1.74; 95% CI: 1.09-2.77) were associated with an increased risk for recurrences in patients with minor risk factors, not in those with major risk factors. CONCLUSIONS: Patients with raised d-dimer levels after discontinuing anticoagulant therapy for VTE provoked by a minor transient risk factor were at an increased risk for recurrences.

The effect of anastomosis time on outcome in recipients of kidneys donated after brain death: a cohort study.

Whether warm ischemia during the time to complete the vascular anastomoses determines renal allograft function has not been investigated systematically. We investigated the effect of anastomosis time on allograft outcome in 669 first, single kidney transplantations from brain-dead donors. Anastomosis time independently increased the risk of delayed graft function (odds ratio per minute [OR] 1.05, 95% confidence interval [CI] 1.02-1.07, p < 0.001) and independently impaired allograft function after transplantation (p = 0.009, mixed-models repeated-measures analysis). In a subgroup of transplant recipients, protocol-specified biopsies at 3 months (n = 186), 1 year (n = 189), and 2 years (n = 153) were blindly reviewed. Prolonged anastomosis time independently increased the risk of interstitial fibrosis and tubular atrophy on these protocol-specified biopsies posttransplant (p < 0.001, generalized linear models). In conclusion, prolonged anastomosis time is not only detrimental for renal allograft outcome immediately after transplantation, also longer-term allograft function and histology are affected by the duration of this warm ischemia.

Obesity in haemophilia patients: effect on bleeding frequency, clotting factor concentrate usage, and haemostatic and fibrinolytic parameters.

The prevalence of obesity in patients with haemophilia (PWH) is increasing. We investigated the effect of obesity on bleeding frequency and clotting factor concentrate (CFC) usage in PWH and assessed whether prothrombotic changes observed in obesity differ between controls and PWH. Number of bleeds and CFC usage were compared between obese (N = 51) and non-obese (N = 46) haemophilia A patients. Markers of haemostasis and fibrinolysis were compared between PWH, and gender-, age- and body mass index (BMI)-matched non-haemophilic controls (N = 91). Median number of bleeds/patient-month was comparable between obese and non-obese patients with severe haemophilia (P = 0.791). Obese patients with severe haemophilia used 1.4 times more CFC/patient-month than non-obese patients (P = 0.036). When adjusting for weight this difference disappeared (P = 0.451). von Willebrand factor plasma concentration (VWF:Ag), factor VIII activity and endogenous thrombin potential were higher in obese than in non-obese controls. Obesity did not influence these markers in PWH. Plasminogen activator inhibitor type 1 levels were higher in obese vs. non-obese PWH (P < 0.001), whereas levels were comparable between PWH and controls (P = 0.912). Plasmin-α2-antiplasmin complex (PAP) levels appeared to be lower in obese vs. non-obese subjects, both within controls (P = 0.011) and PWH (P = 0.008). However, in PWH, PAP levels were higher than in controls (P < 0.001). Obesity is associated with an increase in net CFC usage in PWH, but has no effect on bleeding frequency. In addition, obesity attenuates hyperfibrinolysis in PWH. Future research investigating whether obese PWH need CFC treatment dosed on weight or whether a lower dosage would suffice to prevent and treat bleedings is needed.

[Rivaroxaban: Xarelto--recommendations for pharmacists]. / Le Rivaroxaban (Xarelto): guide de la pratique officinale.

Rivaroxaban is one of the new oral anticoagulants (NOACs). It has many potential advantages in comparison with Vitamin K Antagonists (VKA). It has a predictable anticoagulant effect and does not theoretically require biological monitoring. It is also characterized by less food and drug interactions. However, due to major risks associated with over- and under-dosage, its optimal use in patients should be carefully followed by health care professionals. The aim of this article is to provide recommendations for pharmacists on the practical use of Xarelto in its different approved indications. This document is adapted from the practical user guide of rivaroxaban which was developed by an independent group of Belgian experts in the field of thrombosis and haemostasis.

Penetration of a fractured Bird's Nest filter strut into the liver parenchyma: report of two cases.

This report deals with two rare but similar cases of asymptomatic fracture of a Bird's Nest inferior vena cava (IVC) filter strut, penetrated into the liver parenchyma. Follow-up over 4 and 6 years, respectively, could not reveal any changes in the position of the fragmented strut in the liver parenchyma or any evidence of clinical symptoms owing to the migrated strut fragment.

Does medical specialty influence the treatment of asymptomatic carotid stenosis? a Belgian multidisciplinary survey.

AIM: The aim of this study was to supplement the few data that exist regarding the potential effect of the referring medical specialty on the proposed treatment for asymptomatic carotid stenosis. METHODS: In a web survey, we presented Belgian cardiologists, neurologists and vascular surgeons with two fairly uncomplicated case vignettes on asymptomatic carotid stenosis differing only in the degree of stenosis (70-80% in case 1 and >80% in case 2). RESULTS: In both cases the suggested therapies were different per medical specialty (P<0.000002 and P<0.00002, respectively). Cardiologists were more conservative and vascular surgeons were more aggressive. Preferred therapies for both cases differed statistically significantly (odds ratio 8.63; 95% confidence interval 5.11-14.58). Suggesting a different therapy or not for case 1 and case 2 was also different per medical specialty (P<0.035). Cardiologists were most inclined to suggest a different therapy and vascular surgeons the least. Nobody switched to a more conservative treatment. Younger physicians suggested a more conservative approach (P<0.014). CONCLUSION: Different medical specialties prefer different treatments for asymptomatic carotid stenosis. Also, younger physicians seem more conservative. We elaborate on the different reasons that could explain these findings.

Periprocedural bridging of anticoagulation.

When deciding to preoperatively interrupt--and potentially substitute--a chronic treatment with antithrombotics or not, the surgical or anesthetic bleeding risk of continuing or substituting treatment should be balanced against the risk of thrombosis in case treatment is not interrupted or substituted. The decision will primarily be based upon the initial indication to antithrombotic treatment and the nature of the planned procedure.

Antiplatelet therapy in the perioperative period.

Antiplatelet drugs are the cornerstone treatment in the secondary prevention of arterial thrombosis. Until recently, their intake was interrupted in the perioperative period because of fear for bleeding, but new insights have challenged this old habit: In patients at high risk for atherothrombotic events who need to undergo surgery or an invasive procedure, the risk for bleeding complications because of a treatment with low-dose acetylsalicylic acid (LD ASA) needs to be balanced against the risk of atherothrombotic events after treatment discontinuation. For patients at high risk of atherothrombotic complications recent guidelines do no longer advocate to interrupt LD ASA routinely. However, the likelihood of bleeding versus atherothrombotic complications should be considered on a case-by-case basis. When continued perioperatively, the bleeding risk associated with thienopyridines (ticlopidine, clopidogrel and prasugrel) is higher than that of LD ASA. It is recommended to stop their intake 1 week before the surgical intervention, except in patients with (recent) coronary stenting.

A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study.

BACKGROUND: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. METHODS: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. DISCUSSION: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. TRIAL REGISTRATION: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

Edoxaban for treatment of venous thromboembolism in patient groups with different types of cancer: Results from the Hokusai VTE Cancer study.

BACKGROUND: The safety and efficacy of edoxaban and dalteparin is unclear for several cancer groups. METHODS: We evaluated the occurrence of the primary outcome in large cancer groups. The primary outcome was the composite of recurrent VTE or major bleeding over 12 months. RESULTS: In patients with gastrointestinal cancer, the primary outcome occurred in 19.4% patients given edoxaban and in 15.0% given dalteparin (risk difference [RD], 4.4%; 95%-CI, -4.1% to 12.8%). The corresponding rates for edoxaban and dalteparin were 10.4% and 10.7% for lung cancer (RD, -0.3%; 95%-CI, -10.0% to 9.5%), 13.6% and 12.5% for urogenital cancer (RD, 1.1; 95%-CI, -10.1-12.4), 3.1% and 11.7% for breast cancer (RD, -8.6; 95%-CI, -19.3-2.2), 8.9% and 10.9% for hematological malignancies (RD, -2.0; 95%-CI, -13.1-9.1), and 10.4% and 17.4% for gynecological cancer (RD, -7.0; 95%-CI, -19.8-5.7). In the subgroup of gastrointestinal cancer, edoxaban was associated with a 3.5% lower absolute risk of recurrent VTE and a 7.9% higher risk of major bleeding. CONCLUSION: Edoxaban has a similar risk-benefit ratio to dalteparin in most cancer groups. In those with gastrointestinal cancer, the lower risk of recurrent VTE and the advantages of oral therapy need to be balanced against the increased risk of major bleeding.

Outcome of carotid artery stenting at 2 years follow-up: comparison of nitinol open cell versus stainless steel closed cell stent design.

AIM: The aim of this study was to compare the clinical and ultrasound outcome of carotid artery stenting at 2-year follow-up in patients treated with open-cell nitinol stents versus patients treated with closed cell stainless steel stents. METHODS: This was a non-randomized, retrospective study including 123 patients in whom 132 carotid stent-procedures were performed. Nine patients were treated bilaterally. All patients presented with severe asymptomatic (80%) or symptomatic (>70%) carotid artery stenosis and were treated by carotid angioplasty and stent placement with or without filter embolic protection system. Follow-up consisted of physical evaluation at 1, 6, 12 and 24 months and assessment of the stent patency by ultrasound examination at 6, 12 and 24 months after the stent procedure. RESULTS: In 72 procedures a closed cell stainless steel stent was implanted, in the remaining 60 procedures an open cell nitinol stent was placed. In 8 patients with a stainless steel stent (11%) and in 6 patients with a nitinol stent (10%) a stroke occurred during the follow-up period (P=0.79). Ultrasound examination revealed an in-stent restenosis of 50% to 80% in the stainless steel group (N.=9, 15%) and in the nitinol group (N.=10, 17%) (P=0.7). CONCLUSIONS: At 2-year follow-up after carotid artery stenting, there is no difference in clinical outcome or in stent patency among patients treated with open versus closed cell design stents. Subsequently the type of carotid stent design does not seem to impact the overall midterm outcome after carotid artery stenting.

Tranexamic acid to reduce bleeding after dental extraction in patients treated with non-vitamin K oral anticoagulants: design and rationale of the EXTRACT-NOAC trial.

Bleeding after dental extraction in patients treated with non-vitamin K oral anticoagulants (NOAC) may lead to unplanned reinterventions and interruption of anticoagulation, thereby exposing patients to a risk of thromboembolism. We have designed a study (EXTRACT-NOAC) to investigate whether tranexamic acid (TXA) mouthwash decreases bleeding after extraction in such patients. The study is a randomised, double-blind, placebo-controlled trial. We plan to randomise 236 patients listed for dental extraction and treated with NOAC to 10% TXA mouthwash or placebo. Patients are instructed to use the mouthwash before the dental extraction, and three times a day for three days thereafter. The primary outcome is oral bleeding. Secondary outcomes include type of bleeding, procedural bleeding score, number of reinterventions after oral bleeding, and number of interruptions in NOAC treatment. Any bleeding from sources other than the mouth, and thrombotic events, are recorded as safety outcomes. Patients are followed-up for seven days. This study will provide evidence to guide the management of patients taking NOAC who need teeth extracted.

Staphylococcus aureus, master manipulator of the human hemostatic system.

The coagulation system does not only offer protection against bleeding, but also aids in our defense against invading microorganisms. The hemostatic system and innate immunity are strongly entangled, which explains why so many infections are complicated by either bleeding or thrombosis. Staphylococcus aureus (S. aureus), currently the most deadly infectious agent in the developed world, causes devastating intravascular infections such as sepsis and infective endocarditis. During these infections S. aureus comes in close contact with the host hemostatic system and proves to be a master in manipulating coagulation. The coagulases of S. aureus directly induce coagulation by activating prothrombin. S. aureus also manipulates fibrinolysis by triggering plasminogen activation via staphylokinase. Furthermore, S. aureus binds and activates platelets and interacts with key coagulation proteins such as fibrin(ogen), fibronectin and von Willebrand factor. By manipulating the coagulation system S. aureus gains a significant advantage over the host defense mechanisms. Studying the interplay between S. aureus and the hemostatic system can therefore lead to new innovative therapies for battling S. aureus infections.

Acute non-cirrhotic portal vein thrombosis : review.

A 35-year-old man with a medical history of myocardial infarction, presenting with fever, general malaise and vague abdominal discomfort, was diagnosed with a portomesenteric venous thrombosis and acute cytomegalovirus (CMV) infection. Thrombophilia screening resulted in detection of heterozygosity for factor II G20210A gene mutation. Low molecular weight heparin in therapeutic dose was started, followed by disappearance of thrombus on imaging CT two months after diagnosis. The multifactorial origin of portal thrombosis and the importance of awareness of the link between CMV infection and an increased risk of thrombosis is emphasized with this case and review of the literature. Identifying CMV infection as a trigger for thrombosis can help to avoid extended anticoagulation. Acute non-cirrhotic PVT is a rare but probably underestimated condition as symptoms may be discrete or non-specific. The origin of portal thrombosis is frequently multifactorial. Recent literature has emphasized the increasing prevalence of CMV-induced PVT in immunocompetent patients. The multifactorial origin of portal thrombosis and the importance of awareness of the link between CMV infection and an increased risk of thrombosis is emphasized with this review of the literature and included case. Identifying CMV infection as a trigger for thrombosis can help to avoid extended anticoagulation.

Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians.

Click to hear Dr Baglin's perspective on the role of the laboratory in treatment with new oral anticoagulants SUMMARY: One of the key benefits of the direct oral anticoagulants (DOACs) is that they do not require routine laboratory monitoring. Nevertheless, assessment of DOAC exposure and anticoagulant effects may become useful in various clinical scenarios. The five approved DOACs (apixaban, betrixaban, dabigatran etexilate, edoxaban and rivaroxaban) have different characteristics impacting assay selection and the interpretation of results. This article provides an updated overview on (i) which test to use (and their advantages and limitations), (ii) when to assay DOAC levels, (iii) how to interpret the results relating to bleeding risk, emergency situations and perioperative management, and (iv) what is the impact of DOACs on routine and specialized coagulation assays. Assays for anti-Xa or anti-IIa activity are the preferred methods when quantitative information is useful, although the situations in which to test for DOAC levels are still debated. Different reagent sensitivities and variabilities in laboratory calibrations impact assay results. International calibration standards for all specific tests for each DOAC are needed to reduce the inter-laboratory variability and allow inter-study comparisons. The impact of the DOACs on hemostasis testing may cause false-positive or false-negative results; however, these can be minimized by using specific assays and collecting blood samples at trough concentrations. Finally, prospective clinical trials are needed to validate the safety and efficacy of proposed laboratory thresholds in relation to clinical decisions. We offer recommendations on the tests to use for measuring DOACs and practical guidance on laboratory testing to help patient management and avoid diagnostic errors.

The adsorption of dabigatran is as efficient as addition of idarucizumab to neutralize the drug in routine coagulation assays.

INTRODUCTION: The direct thrombin inhibitor dabigatran interferes with thrombophilia screening and with the diagnosis of hemostasis disorders that develop during treatment with the anticoagulant. In vitro addition of idarucizumab, a humanized antibody fragment that binds dabigatran, to plasma samples containing dabigatran fully neutralizes the drug. This study was carried out to determine whether binding of dabigatran on selected insoluble commercial adsorbent material, DOAC-STOPR , was as efficient as idarucizumab to neutralize the anticoagulant activity of the drug in vitro. METHODS: Coagulation assays sensitive to dabigatran were carried out with patient and control plasma samples spiked with dabigatran and supplemented with idarucizumab or incubated with adsorbent material. RESULTS: In samples containing upto 10 000 ng/mL dabigatran, the adsorption procedure was at least as efficient as the addition of idarucizumab to neutralize the activity of the anticoagulant drug. Neither the adsorption procedure nor the addition of idarucizumab did impair routine coagulation assays carried out with plasma devoid of dabigatran, such as the activated partial thromboplastin time, prothrombin time, fibrinogen Clauss, and the thrombophilia screening assays used to detect antiphospholipid antibodies or activated protein C resistance. In addition, the adsorption procedure did not interfere with the detection of lupus anticoagulant samples. CONCLUSIONS: Adsorption of dabigatran in plasma samples containing the drug neutralizes its activity as efficiently as the addition of idarucizumab. This method allows the evaluation of thrombophilia markers without interruption of anticoagulation therapy or the detection of hemostasis disorders in patients treated with the drug.

Age-adjusted D-dimer to rule out deep vein thrombosis: findings from the PALLADIO algorithm.

Essentials The accuracy of the age-adjusted D-dimer in suspected venous thromboembolism is still debated. We assessed the performance of age-adjusted D-dimer combined with the PALLADIO algorithm. The age-adjusted threshold can reduce the need for imaging tests compared to the fixed cut-off. The safety of this approach should be confirmed in large management studies. SUMMARY: Background Age-adjusted D-dimer has been proposed to increase specificity for the diagnosis of venous thromboembolism (VTE). However, the accuracy of this threshold has been recently questioned. Objectives To assess the diagnostic performance of age-adjusted D-dimer combined with clinical pretest probability (PTP) in patients with suspected deep vein thrombosis (DVT). Methods PALLADIO (NCT01412242) was a multicenter management study that validated a new diagnostic algorithm, incorporating PTP, D-dimer (using the manufacturer's cut-off) and limited or extended compression ultrasonography (CUS) in outpatients with clinically suspected DVT. Patients with unlikely PTP and negative D-dimer had DVT ruled out without further testing (group 1); patients with likely PTP or positive D-dimer underwent limited CUS (group 2); patients with likely PTP and positive D-dimer underwent extended CUS (group 3). Patients with DVT ruled out at baseline had a 3-month follow-up. In this post-hoc analysis we evaluated age-adjusted D-dimer cut-off (defined as age times 10 µg L-1 , or age times 5 µg L-1 for D-dimers with a lower manufacturer's cut-off, in patients > 50 years). Results In total, 1162 patients were enrolled. At initial visit, DVT was detected in 4.0% of patients in group 2 and 53.0% in group 3. The age-adjusted D-dimer, compared with the fixed cut-off, resulted in 5.1% (95% CI, 4.0-6.5%) reduction of CUS. The incidence of symptomatic VTE during follow-up was: 0.24% (95% CI, 0.04-1.37) in group 1; 1.12% (95% CI, 0.44-2.85) in group 2; and 1.89% (95% CI, 0.64-5.40) in group 3. Conclusions The PALLADIO algorithm using age-adjusted D-dimer slightly decreased the number of required imaging tests, but this approach should be confirmed in large management studies.

An open conformation of ADAMTS-13 is a hallmark of acute acquired thrombotic thrombocytopenic purpura.

Essentials Conformational changes in ADAMTS-13 are part of its mode-of-action. The murine anti-ADAMTS-13 antibody 1C4 discriminates between folded and open ADAMTS-13. ADAMTS-13 conformation is open in acute acquired thrombotic thrombocytopenic purpura (TTP). Our study forms an important basis to fully elucidate the pathophysiology of TTP. SUMMARY: Background Acquired thrombotic thrombocytopenic purpura (aTTP) is an autoimmune disorder characterized by absent ADAMTS-13 activity and the presence of anti-ADAMTS-13 autoantibodies. Recently, it was shown that ADAMTS-13 adopts a folded or an open conformation. Objectives As conformational changes in self-antigens play a role in the pathophysiology of different autoimmune diseases, we hypothesized that the conformation of ADAMTS-13 changes during acute aTTP. Methods Antibodies recognizing cryptic epitopes in the spacer domain were generated. Next, the conformation of ADAMTS-13 in 40 healthy donors (HDs), 99 aTTP patients (63 in the acute phase versus 36 in remission), 12 hemolytic-uremic syndrome (HUS) patients and 63 sepsis patients was determined with ELISA. Results The antibody 1C4 recognizes a cryptic epitope in ADAMTS-13. Therefore, we were able to discriminate between a folded and an open ADAMTS-13 conformation. We showed that ADAMTS-13 in HDs does not bind to 1C4, indicating that ADAMTS-13 circulates in a folded conformation. Similar results were obtained for HUS and sepsis patients. In contrast, ADAMTS-13 of acute aTTP patients bound to 1C4 in 92% of the cases, whereas, in most cases, this binding was abolished during remission, showing that the conformation of ADAMTS-13 is open during an acute aTTP episode. Conclusions Our study shows that, besides absent ADAMTS-13 activity and the presence of anti-ADAMTS-13 autoantibodies, an open ADAMTS-13 conformation is also a hallmark of acute aTTP. Demonstrating this altered ADAMTS-13 conformation in acute aTTP will help to further unravel the pathophysiology of aTTP and lead to improved therapy and diagnosis.