A systematic review of the evidence supporting post-operative antithrombotic use following cardiopulmonary bypass in children with CHD

Objectives: To determine the optimal antithrombotic agent choice, timing of initiation, dosing and duration of therapy for paediatric patients undergoing cardiac surgery with cardiopulmonary bypass. Methods: We used PubMed and EMBASE to systematically review the existing literature of clinical trials involving antithrombotics following cardiac surgery from 2000 to 2020 in children 0–18 years. Studies were assessed by two reviewers to ensure they met eligibility criteria. Results: We identified 10 studies in 1929 children across three medications classes: vitamin K antagonists, cyclooxygenase inhibitors and indirect thrombin inhibitors. Four studies were retrospective, five were prospective observational cohorts (one of which used historical controls) and one was a prospective, randomised, placebo-controlled, double-blind trial. All included were single-centre studies. Eight studies used surrogate biomarkers and two used clinical endpoints as the primary endpoint. There was substantive variability in response to antithrombotics in the immediate post-operative period. Studies of warfarin and aspirin showed that laboratory monitoring levels were frequently out of therapeutic range (variably defined), and findings were mixed on the association of these derangements with bleeding or thrombotic events. Heparin was found to be safe at low doses, but breakthrough thromboembolic events were common. Conclusion: There are few paediatric prospective randomised clinical trials evaluating antithrombotic therapeutics post-cardiac surgery; most studies have been observational and seldom employed clinical endpoints. Standardised, validated endpoints and pragmatic trial designs may allow investigators to determine the optimal drug, timing of initiation, dosing and duration to improve outcomes by limiting post-operative morbidity and mortality related to bleeding or thrombotic events.

Screening of the Promising Direct Thrombin Inhibitors from Haematophagous Organisms. Part I: Recombinant Analogues and Their Antithrombotic Activity In Vitro

The success in treatment of venous thromboembolism and acute coronary syndromes using direct thrombin inhibitors has stimulated research aimed at finding a new anticoagulant from haematophagous organisms. This study deals with the comparison between hirudin-1 from Hirudomedicinalis(desirudin), being the first-known and most well-studied natural anticoagulant, along with recombinant analogs of haemadin from the leech Haemadipsa sylvestris, variegin from the tick Amblyomma variegatum, and anophelin from Anopheles albimanus. These polypeptides were chosen due to their high specificity and affinity for thrombin, as well as their distinctive inhibitory mechanisms. We have developed a universal scheme for the biotechnological production of these recombinant peptides as pharmaceutical substances. The anticoagulant activities of these peptides were compared using the thrombin amidolytic activity assay and prolongation of coagulation time (thrombin time, prothrombin time, and activated partial thromboplastin time) in mouse and human plasma. The preliminary results obtained suggest haemadin as the closest analog of recombinant hirudin-1, the active substance of the medicinal product Iprivask (Aventis Pharmaceuticals, USA) for the prevention of deep venous thrombosis in patients undergoing elective hip or knee replacement surgery. In contrast, variegin can be regarded as a natural analog of bivalirudin (Angiomax, The Medicines Company), a synthetic hirudin-1 derivative certified for the treatment of patients undergoing percutaneous coronary intervention and of patients with unstable angina pectoris after percutaneous transluminal coronary angioplasty.

Direct oral anticoagulant (DOAC) interference in hemostasis assays

Direct oral anticoagulants (DOACs) are a group of direct coagulation factor inhibitors including both direct thrombin inhibitors and direct factor Xa inhibitors. These medications may cause hemostasis assay interference by falsely increasing or decreasing measured values, depending on the analyte. Considering the potential for DOAC interference in a variety of hemostasis assays is essential to avoid erroneous interpretation of results. Preanalytic strategies to avoid DOAC interference include selecting alternatives to clot-based hemostasis assays in patients taking DOACs when possible and sample collection timed when the patient is off anticoagulant therapy or at the expected drug trough. Clinical laboratories may also provide educational materials that clearly describe possible interferences from DOAC, develop testing algorithms to aid in detection of DOAC in submitted samples, use DOAC-neutralizing agents to remove DOACs before continuing with testing, and write interpretive comments that explain the effects of DOAC interference in hemostasis tests. Using a combination of the described strategies will aid physicians and laboratorians in correctly interpreting hemostasis and thrombosis laboratory tests in the presence of DOACs.

Direct oral anticoagulants; a review for the non-specialist

Thrombin inhibitors and direct factor Xa inhibitors represent a major breakthrough in the field of anticoagulation pharmacotherapy. These novel agents have replaced warfarin as the oral anticoagulant of choice in certain indications, as they possess equal or superior efficacy and better safety profiles. They have a quick onset of action, predictable pharmacokinetic properties and minimal drug and food interactions. So they do not require frequent blood monitoring and dose adjustments as with warfarin. Considering all the advantages, there seems to be a rapid increase in the number of patients who are started on these novel anticoagulants. In this review, we highlight the pharmacology of these direct oral anticoagulants and the evidence-based indications for their use. We aim to provide a clinical overview for the non-specialist who may be called upon to manage a patient who is currently on one of these novel anticoagulants.

Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors

Despite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-of-care parenteral anticoagulants for percutaneous coronary intervention (PCI). We discovered novel direct thrombin inhibitors (DTIs) from tick salivary transcriptomes and optimised their pharmacologic activity. The most potent, ultravariegin, inhibits thrombin with a Ki of 4.0 pM, 445-fold better than bivalirudin. Unexpectedly, despite their greater antithrombotic effect, variegin/ultravariegin demonstrated less bleeding, achieving a 3-to-7-fold wider therapeutic index in rodent thrombosis and bleeding models. When used in combination with aspirin and ticagrelor in a porcine model, variegin/ultravariegin reduced stent thrombosis compared with antiplatelet therapy alone but achieved a 5-to-7-fold lower bleeding time than UFH/bivalirudin. Moreover, two antibodies screened from a naïve human antibody library effectively reversed the anticoagulant activity of ultravariegin, demonstrating proof-of-principle for antidote reversal. Variegin and ultravariegin are promising translational candidates for next-generation DTIs that may reduce peri-PCI bleeding in the presence of antiplatelet therapy.

Analysis of Inter-Observer Agreement of Adjudication of Colors of Pad Colors of Doac Dipstick to Determine Presence or Absence of Direct Oral Anticoagulants in Outpatients' Urine Samples

Background: The efficacy and safety of direct oral anticoagulants (DOACs) in patients with thromboembolic disease is closely related to patient's adherence to therapy. Objective documentation of drug intake is a useful tool for patients' education and improvement of adherence to treatment but may be improved by accurate point-of-care (POCT) testing. Results of DOAC Dipstick may be one of these methods but may depend on interpretation variability. Aim: We aim to analyze the inter-observer agreement of DOAC Dipstick near-patient device in outpatients on stable anticoagulation with rivaroxaban (R), apixaban (A) and dabigatran (D). Methods: A prospective observational cohort study was performed including patients on active treatment with R, A, and D for secondary VTE prevention. All participants were routinely assessed for DOACs' plasma concentration using STA ® Liquid anti-Xa and STA ® Liquid anti-IIa chromogenic assays , and creatinine clearance (Cockroft -Gault equation). DOAC Dipstick test was performed in patients' urine samples were performed by trained staff according the instructions for use. The assessment was based on pads'colors which are specific for indicating the presence and absence of factor -Xa (FXA) and thrombin inhibitors (THI). In order to assess inter-observer agreement, the study nurse performing the test and the medication-prescribing physician were in charge of evaluating independently each test strip. THI pad and FXA pad served as negative control for patients treated with R and A, and D, respectively. Inter-observer agreement was calculated by Cohen's kappa coefficient (kappa index). Results: A new interim analysis shortly before study termination was performed after enrolment of 79 patients (female/ male 44/35, age 56 ± 18 years, mean and standard deviation). Of those, 20% (n=17) were treated for deep vein thrombosis, 13% (n=10) for pulmonary embolism (PE), 40% (n=32) for recurrent thromboembolic disease, 18.3% (n=13), for cancer-associated thrombosis, 6 for antiphospholipid syndrome (n= 5), 2 % (n=2) for AF. 60 % (n=48 ) were treated with R, 37% (n=29) with A and 3% (n=2) with D. All patients had normal renal function. Anti-factor Xa levels were determined with a median value of 156.6±129.2 ng/ml and anti-factor IIa levels with 191.66±110.34 ng/mL. The inter- observer agreement of colors of FXA and THI pads of urine samples was 0.99 for positivity for R, A, and D. Pads that served as negative controls were assessed correctly as negative by both observers in all cases (kappa index 1.0). Conclusion: Given the encouraging results, the ongoing study should allow the device's validation as an accurate, easy-to-use assessment tool for determination of the presence or absence of DOACs in patients' urine samples also based on a very low inter-observer variability. The aforementioned data confirm the results of the first interim analysis presented in the ISTH 2021 congress. Disclosures Harenberg: DOACSENCE: Other: Founder and managing director.

Global research status and trends in venous thromboembolism after hip or knee arthroplasty from 1990 to 2021: a new perspective (Preprint)

BACKGROUND Venous thromboembolism (VTE) after hip or knee arthroplasty has attracted increasing attention over the past few decades. However, there is no bibliometric report on the publications in this field. OBJECTIVE The purpose of this study was to analyze the global research status, hotspots, and trends in VTE after arthroplasty. METHODS All articles about VTE research after hip or knee arthroplasty from 1990 to 2021 were retrieved from the Web of Science Core Collection database. The information of each article including citation, title, author, journal, country, institution, and keywords, was extracted for bibliometric analysis. RESULTS A total of 1,245 original articles from 53 countries and 603 institutions were retrieved. The number of publications showed a rising trend, with the largest contributions made by the USA. McMaster University in Canada was the leading institution for publications. The most productive author in this field was Eriksson BI, followed by Lassen MR and Dahl OE. The journals with the highest output and highest citation were the Journal of Arthroplasty and the Thrombosis and Haemostasis, respectively. The research hotspots switched from VTE diagnosis and heparin to factor Xa inhibitors (fondaparinux, rivaroxaban, apixaban) and direct thrombin inhibitors (dabigatran etexilate, ximelagatran), and finally to aspirin, risk factor studies, which can be observed from the keyword analysis and co-cited reference cluster analysis. CONCLUSIONS Over the past few decades, the understanding of VTE after hip or knee arthroplasty has been improved significantly. VTE prophylaxis agents have attracted tremendous attention, including warfarin, low molecular weight heparin, oral direct factor Xa inhibitors, oral direct thrombin inhibitors, and aspirin. These studies exert a critical influence on decision-making and management for VTE. Additionally, individualized VTE prevention based on risk factors for each patient and the development of new safe, effective, and inexpensive oral agents will be emerging trends in the future.

Exosite Binding in Thrombin: A Global Structural/Dynamic Overview of Complexes with Aptamers and Other Ligands

Thrombin is the key enzyme of the entire hemostatic process since it is able to exert both procoagulant and anticoagulant functions; therefore, it represents an attractive target for the developments of biomolecules with therapeutic potential. Thrombin can perform its many functional activities because of its ability to recognize a wide variety of substrates, inhibitors, and cofactors. These molecules frequently are bound to positively charged regions on the surface of protein called exosites. In this review, we carried out extensive analyses of the structural determinants of thrombin partnerships by surveying literature data as well as the structural content of the Protein Data Bank (PDB). In particular, we used the information collected on functional, natural, and synthetic molecular ligands to define the anatomy of the exosites and to quantify the interface area between thrombin and exosite ligands. In this framework, we reviewed in detail the specificity of thrombin binding to aptamers, a class of compounds with intriguing pharmaceutical properties. Although these compounds anchor to protein using conservative patterns on its surface, the present analysis highlights some interesting peculiarities. Moreover, the impact of thrombin binding aptamers in the elucidation of the cross-talk between the two distant exosites is illustrated. Collectively, the data and the work here reviewed may provide insights into the design of novel thrombin inhibitors.

Pediatric Mechanical Circulatory Support: Pathophysiology of Pediatric Hemostasis and Available Options

Pediatric mechanical circulatory support (MCS) is considered a strategy for heart failure management as a bridge to recovery and transplantation or as a destination therapy. The final outcome is significantly impacted by the number of complications that may occur during MCS. Children on ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO) are at high risk for bleeding and thrombotic complications that are managed through anticoagulation. The first detailed guideline in pediatric VADs (Edmonton Anticoagulation and Platelet Inhibition Protocol) was based on conventional antithrombotic drugs, such as unfractionated heparin (UFH) and warfarin. UFH is the first-line anticoagulant in pediatric MCS, although its profile is not considered optimal in pediatric setting. The broad variation in heparin doses among children is associated with frequent occurrence of cerebrovascular accidents, bleeding, and thrombocytopenia. Direct thrombin inhibitors (DTIs) have been utilized as alternative strategies to heparin. Since 2018, bivalirudin has become the chosen anticoagulant in the long-term therapy of patients undergoing MCS implantation, according to the most recent protocols shared in North America. This article provides a review of the non-traditional anticoagulation strategies utilized in pediatric MCS, focusing on pharmacodynamics, indications, doses, and monitoring aspects of bivalirudin. Moreover, it exposes the efforts and the collaborations among different specialized centers, which are committed to an ongoing learning in order to minimize major complications in this special pediatric population. Further prospective trials regarding DTIs in a pediatric MCS setting are necessary and in specific well-designed randomized control trials between UFH and bivalirudin. To conclude, based on the reported literature, the clinical use of the bivalirudin in pediatric MCS seems to be a value added in controlling and maybe reducing thromboembolic complications. Further research is necessary to confirm all the results provided by this literature review.