Lupus anticoagulant, warfarin, and alternative laboratory monitoring of anticoagulation

Guidelines on the investigation and management of the antiphospholipid syndrome.

This guidance updates and replaces the previous guideline on the investigation and management of antiphospholipid syndrome (APS) published in 2000 (Greaves et al, 2000), though where there have not been changes we refer back to them when appropriate. The guidance is updated with reference to relevant publications since 2000. Publications known to the writing group were supplemented with additional papers identified by searching PubMed for publications in the last 11 years using the key words: lupus anticoagulant, anticardiolipin, antiphospholipid, b2–glycoprotein I, antiprothrombin and limits (clinical trial, randomized control trial, meta-analysis, humans, core clinical journals, English language). The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the Royal College of Obstetricians and Gynaecologists (RCOG), and the British Committee for Standards in Haematology (BCSH) Committee and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMEN DATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with antiphospholipid syndrome though individual patient circumstances may dictate an alternative approach.

Recommendations for Evaluation of Prosthetic Valves With Echocardiography and Doppler Ultrasound: A Report From the American Society of Echocardiography's Guidelines and Standards Committee and the Task Force on Prosthetic Valves, Developed in Conjunction With the American College of Cardiology Cardiovascular Imaging Committee, Cardiac Imaging Committee of the American Heart Association, the European Association of Echocardiography, a registered branch of the

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To review the available literature on international normalized ratio (INR) and chromogenic factor X (CFX) monitoring in patients with antiphospholipid syndrome (APS), specifically lupus anticoagulant (LA), and furthermore, to identify benefits of one monitoring test compared with the other in the presence of LA. A literature search was conducted through MEDLINE (1946-May 2014) utilizing the following MeSH terms chromogenic compounds, anticoagulants, and factor X. Further articles were identified from original literature citations. All English-language studies were included that involved INR and/or CFX monitoring in APS patients that focused on a therapeutic anticoagulation level with warfarin therapy. A total of 55 articles were identified, of which nine are referenced because of their relevance for this review: three articles focus on the efficacy of utilizing INR monitoring in patients with APS, five focus on CFX compared with INR for therapeutic warfarin dosing, and one compares different thromboplastins utilizing both INR and CFX monitoring. INR monitoring in patients with APS, specifically LA, was not found to be reliable because thromboplastin reagents are sensitive to LA. Furthermore, when INR was compared to CFX, patients with LA had supratherapeutic INRs despite having CFX within goal range. In a subgroup of APS patients, INR monitoring may not be safe for determining the dose of warfarin because their INR values can be falsely elevated. Although CFX monitoring is more accurate, it too comes with its own downsides. Managing warfarin therapy in the APS population needs to be individualized.

The International Normalized Ratio (INR) is generally recommended to monitor anticoagulant therapy in patients treated with warfarin. However, there has been concern about the validity of the INR to monitor warfarin therapy in patients with lupus anticoagulant, particularly when there is prolongation of the baseline INR. An alternative approach is to use a chromogenic factor X assay that is not sensitive to lupus anticoagulant. However, this assay is expensive, not widely available, and does not have an established therapeutic range. We hypothesized that the phospholipid-rich dilute Russell viper venom time (prdRVVT), a simple, rapid and inexpensive assay, might be suitable to monitor warfarin therapy in this situation since Russell's viper venom directly activates coagulation factor X while the phospholipid in the reagent reduces or negates any effect of lupus anticoagulant on the assay. We measured the INR, chromogenic factor X, and prdRVVT in 50 patients stabilized on warfarin for at least 6 weeks, 12 of whom had lupus anticoagulant, and 37 patients not taking warfarin, 17 of whom had lupus anticoagulant. Factor X was negatively correlated with INR in anticoagulated patients both in the absence (r = -0.45, P = 0.01) and presence (r = -0.43, P = 0.17) of lupus anticoagulant. The prdRVVT was also strongly correlated with INR in anticoagulated patients without lupus anticoagulant (r = 0.60, P < 0.0001) but there was no correlation in the presence of lupus anticoagulant (r = -0.13, P = 0.68). Our results suggest that the prdRVVT is not suitable for monitoring warfarin therapy in patients with lupus anticoagulant.

Aims The purpose of the present analysis was to determine survival rate, and risk for thromboembolic and bleeding complications after mechanical heart valve replacement with St. Jude Medical mechanical heart (bileaflet) valves under differing regimens of postoperative anticoagulation. Method In the randomized German Experience with Low Intensity Anticoagulation (GELIA) study, 553 patients after mitral valve replacement and 158 patients after double valve replacement with a St. Jude Medical prosthesis were randomly assigned to three groups for postoperative oral anticoagulation: group A, target International Normalized Ratio (INR) range 3·0–4·5; group B, target INR range 2·5–4·0; and group C, target INR range 2·0–3·5. Results The various anticoagulation regimens had no significant impact on risk for bleeding or thromboembolism, or cumulative survival rate after mitral valve replacement. However, less intensive anticoagulation (target INR range 2·0–3·5) was associated with a significant decrease in cumulative survival rate after combined valve replacement, although analysis confirmed that 54% of these deaths were not valve related. Conclusion The results suggest that in terms of low-intensity anticoagulation an INR of 2·0–3·5 after mitral valve replacement and of 2·5–4·0 after double valve replacement (aortic and mitral) may be recommended when using the St. Jude Medical bileaflet prosthetic valve.

Background Mechanical prosthetic valve thrombosis (PVT) is a life-threatening complication that requires immediate intervention. With current prosthetic devices and aggressive prophylactic anticoagulation, the incidence of PVT remains low. It needs monitoring of international normalized ratio (INR), which is somewhat difficult to do in rural areas such as West Aceh due to geography. This report details the case of a woman with PVT who developed heart failure after a period of suboptimal anticoagulation. Case Summary We described a 51-year-old woman who had undergone coronary artery bypass graft and mitral valve replacement procedure in 2017. Her physical examination showed the decrease of the prosthetic click sound and lung congestion. From her blood examination, the INR was subtherapeutic. A thrombus was detected on the prosthetic mitral valve by transoesophageal echocardiography. She had history of uncontrolled INR because the patient do not routinely checked her blood to control the optimal dose of anticoagulant. The patient underwent reoperation for mechanical valve thrombosis but unfortunately in the end the patient died at the procedure. Discussion In patients undergoing mechanical heart valve replacement, time in therapeutic range of targeted INR should be ≥ 70 % otherwise it will increase in risk of thromboembolic events. However, in developing countries which have remote areas, repeated examination of the use of warfarin in obtaining the INR target is still a major challenge. Conversely, serious risks can occur if this is not achieved and might be ended up with disaster toward the patient.

Background Mechanical prosthetic valve thrombosis (PVT) is a life-threatening complication that requires immediate intervention. With current prosthetic devices and aggressive prophylactic anticoagulation, the incidence of PVT remains low. It needs monitoring of international normalized ratio (INR), which is somewhat difficult to do in rural areas such as West Aceh due to geography. This report details the case of a woman with PVT who developed heart failure after a period of suboptimal anticoagulation. Case Summary We described a 51-year-old woman who had undergone coronary artery bypass graft and mitral valve replacement procedure in 2017. Her physical examination showed the decrease of the prosthetic click sound and lung congestion. From her blood examination, the INR was subtherapeutic. A thrombus was detected on the prosthetic mitral valve by transoesophageal echocardiography. She had history of uncontrolled INR because the patient do not routinely checked her blood to control the optimal dose of anticoagulant. The patient underwent reoperation for mechanical valve thrombosis but unfortunately in the end the patient died at the procedure. Discussion In patients undergoing mechanical heart valve replacement, time in therapeutic range of targeted INR should be ≥ 70 % otherwise it will increase in risk of thromboembolic events. However, in developing countries which have remote areas, repeated examination of the use of warfarin in obtaining the INR target is still a major challenge. Conversely, serious risks can occur if this is not achieved and might be ended up with disaster toward the patient.

We describe a patient with non-Hodgkin's lymphoma who developed a lupus anticoagulant (LA) detectable by activated partial thromboplastin time (APTT), dilute Russell's viper venom time (DRVVT) and kaolin clotting time (KCT). IgM anticardiolipin antibodies (ACA) were elevated. At a later admission, and following treatment for the lymphoma, routine coagulation screening showed an elevated prothrombin time (PT) without correction in mixing tests using a recombinant thromboplastin. Routine APTT was below the reference range and ACA levels were normal. Raw data for one-stage factor assays demonstrated the presence of an inhibitor. Analysis for LA was undertaken by DRVVT, KCT, activated seven lupus anticoagulant assay, Taipan snake venom time, platelet neutralisation procedures (PNP), Ecarin time and PT using rabbit brain thromboplastin. The results revealed a LA capable of prolonging the clotting times of the PNPs and PT using recombinant thromboplastin, but that was corrected using Ecarin venom, modified PNP and brain thromboplastin. The antibody also demonstrated the lupus anticoagulant co-factor effect. The factor VIII: C was markedly raised which may have masked the LA in the APTT. The changing laboratory profile over time demonstrates the effects of LA heterogeneity and variations in sensitivity and specificity of assays for the detection of antiphospholipid antibodies.

Atrial Fibrillation and Thromboembolism

Oral direct thrombin and Xa inhibitors are worldwide distributed for prevention and treatment of thrombosis. It is important to recognize their effects on lupus anticoagulant (LA) testing. The aim of the study is to describe the rate of false-positive results of LA tests on plasmas of patients with previous negative LA tests results that receive dabigatran etexilate (DAB) 110mg/twice a day, rivaroxaban (RIV) 10mg/day or 15mg/twice a day, or enoxaparin 40mg/day. Blood was taken between 1.5 and 4h post administration. Tests evaluated are as follows: prothrombin time, APTT, dilute Russell viper venom time (DRVVT) screen, APTT, and DRVVT mixing studies, index of circulating anticoagulant (ICA) with normal plasma, screen/confirm normalized ratio (NR) for DRVVT and silica clotting time (SCT). Plasmas from patients taking DAB (n=22) presented 100% prolonged APTT and DRVVT with ICA above the cutoff point and 81.8% positive screen/confirm NR, 100% prolonged SCT screen, but 4.5% positive confirmatory NR. All patients receiving RIV at 15mg/twice a day (n=4) presented positive DRVVT screen, mixing, and confirmatory tests, 75% and 100% prolonged APTT and SCT screen, with negative screen/confirm NR. Those taking RIV 10mg/day (n=22) showed 81.8% prolonged DRVVT screen, 82.3% and 76.5% of them with positive mixing and confirmatory studies. Patients receiving enoxaparin also presented high prevalence of APTT and DRVVT false-positive results. Dabigatran etexilate, RIV, and enoxaparin affect tests for LA not only in screening and mixing, but also in confirmatory studies. We considered that LA testing should not to be performed when patients are taken these drugs, particularly if blood is collected at peak, in order to avoid false-positive results.

Embolized Disc from a Beall Mitral Valve Prosthesis: Real-Time Echocardiographic Identification

Chromogenic Factor X Assay for Monitoring Warfarin Anticoagulation in a Child With a Prosthetic Mitral Valve.

Evaluation of risk factors for stroke/embolism and of complications due to anticoagulant therapy in atrial fibrillation.