Real-life experience of edoxaban treatment for venous thromboembolism (VTE)/pulmonary embolism (PE) in patients with isolated positive Lupus Anticoagulant (LAC) during the COVID-19 pandemic lockdown in Italy.

OBJECTIVE: Direct-acting oral anticoagulants (DOACs) have established indications, according to recent guidelines for the treatment and prevention of venous thromboembolism (VTE), including pulmonary embolism (PE), with a safer profile compared to vitamin K antagonist (VKA) in terms of a lower risk for major bleeding and no need of blood coagulation tests. However, DOACs are not indicated in the treatment of patients with triple-positive antiphospholipid syndrome (APS). This limitation is often extended in clinical practice to patients with isolated positivity. The COVID-19 pandemic has sometimes made it difficult to maintain a safe VKA treatment, due to the practical difficulties of performing INR. PATIENTS AND METHODS: We evaluated 39 patients with a previous unprovoked VTE/PE, who were no longer eligible for VKA treatment due to the difficulty of performing INR during the COVID-19 pandemic lockdown, in Italy. All patients had a positive LAC and refused a long-term anticoagulation with low molecular weight heparin. They were shifted to edoxaban. RESULTS: Any recurrence of VTE/PE occurred during the observation period (up to eight months of treatment), while only one minor bleeding event was recorded (Hazard ratio=0.06, 95% confidence interval 0.03-0.11, p=0.094). No arterial events occurred during the observation period. Hemoglobin, platelets, and creatinine were unchanged during the observation period. CONCLUSIONS: Edoxaban treatment may be safe and effective in preventing the recurrence of VTE/PE in patients with isolated LAC positivity, without the occurrence of arterial events.

How to Achieve Standardization? Diluted Russell Viper Venom Test for Lupus Anticoagulant Detection in a Chinese Female Population.

On an international scale, guidelines and proposals for lupus anticoagulant detection have been published over the last 20 years, but until now, standardization has not been completely realized. The aim of this study was to evaluate the different ways of interpreting the results of lupus anticoagulant detection for standardization. A retrospective review of 15 447 instances of lupus anticoagulant detection by the diluted Russell Viper Venom test for female patients presenting with problems relating to the areas of reproduction, gynecology and obstetrics was performed. Lupus anticoagulant data were compared between different departments, months, reagent lots and cutoffs. Significant differences were found in patient data between different reagent lots, especially between lots of screening reagents (monthly average: highest 37.96 s vs lowest 33.88 s) and in the positive rates of lupus anticoagulant by different detection cutoffs (47.58% by using LA1/LA2 > 1.20 without normalization as a cutoff in Lot 1 vs 1.52% by using LA1 > 44 s as a cutoff in Lot 3). Compared with the cutoff using the value above the 99th percentile of LA1 for the healthy donors per lot, the cutoff using integrated tests with normalization had the smaller deviation of positive rate between different reagent lots. Pregnant women had higher LA1/LA2 levels than nonpregnant women. Based on the results, normalization is needed because there are significant lot-to-lot variations. Integrated tests with normalization might be a better standard by which to confirm lupus anticoagulant. Pregnant women should have population-specific cutoffs because they have higher LA1/LA2 levels.

The effect of DOAC-Stop on lupus anticoagulant testing in plasma samples of venous thromboembolism patients receiving direct oral anticoagulants.

Background Direct oral anticoagulants (DOACs) cause false positive lupus anticoagulant (LA) results. We assessed the impact of DOAC-Stop, reversing in vitro effects of DOACs, on LA testing in anticoagulated patients. Methods We assessed 75 venous thromboembolism patients aged 44.5±14.6 years. Blood samples were collected 2-28 h since intake of DOACs, including 50 patients on rivaroxaban, 20 on dabigatran and five on apixaban. LA testing was performed at baseline and after DOAC-Stop treatment. Positive LA was defined as the normalized (patient/standard plasma clotting time) LA screening and screening (LA1)/confirmation (LA2) ratios exceeding 1.2. Results LA diluted Russell's viper venom time (dRVVT) normalized screening test revealed abnormal results in 73 (97.3%) and activated partial thromboplastin time (APTT)-LA in 49 (65.3%) patients. In six (8%) patients, antiphospholipid syndrome (APS) was diagnosed. dRVVT LA1/LA2 was abnormal in 35 (50.7%) patients taking DOACs. The APTT ratio was normal in all studied subjects. DOAC-Stop completely removed dabigatran and reduced by 98% rivaroxaban and by 92.3% apixaban concentrations (all p<0.05). After DOAC-Stop screening dRVVT remained prolonged in 34 (49.3%) patients (p<0.001), while dRVVT LA1/LA2 was abnormal in six (8.7%) subjects, with no association with DOAC concentrations at baseline and after DOAC-Stop. The APTT-LA screening test remained prolonged in five (7.2%) patients, while the APTT LA1/LA2 ratio was normal in those subjects. DOAC-Stop did not influence LA testing in APS patients. Conclusions Application of DOAC-Stop effectively reduced plasma DOAC concentrations leading to appropriate dRVVT results in up to 97% of VTE patients.

The enigmas of the lupus anticoagulant: mechanisms, diagnosis, and management.

Lupus anticoagulant (LA) is a laboratory abnormality associated with the antiphospholipid syndrome. It is a paradoxical phenomenon in which one or more in vitro diagnostic clotting tests are prolonged and thus seem due to an anticoagulant, whereas the antiphospholipid syndrome is manifest clinically as inappropriate or excessive thrombosis. LA should be suspected when thrombosis, recurrent fetal loss, or a prolonged phospholipid (PL)-dependent clotting test is present without other identifiable causes. Despite the heterogeneity of LA antibodies, a consensus has evolved to identify the LA. Four conditions must be met for this laboratory diagnosis: 1) prolongation of a PL-based clotting test, 2) confirmation of an inhibitor-like pattern in the clotting test, 3) confirmation of PL dependence in coagulation tests, and 4) exclusion of a specific factor inhibitor. Even with an extensive armamentarium for LA diagnosis and treatment, it is still a formidable task.

Long-term remission from life-threatening hypercoagulable state associated with lupus anticoagulant (LA) following rituximab therapy.

Rituximab, a chimeric monoclonal CD20 antibody, is useful in the treatment of B-cell lymphomas and certain autoimmune diseases. We report a successful outcome of rituximab for life threatening hypercoagulable state associated with lupus anticoagulant (LA). A 30-year-old woman initially presented 10 years ago with DVT and positive serology for SLE and LA. While on Coumadin, she suffered from recurrent DVT in the legs and arms, pulmonary emboli, Budd-Chiari syndrome, mesenteric vein thrombosis, bone infarcts, recurrent strokes, and chronic ITP. All measures including plasmapheresis and monthly IV cyclophosphamide were of no benefit. She was recently admitted with spontaneous subdural hematoma with INR of 3.8. Upon discontinuation of anticoagulation for surgical drainage, she developed acute abdomen from thrombosis and recurrent DVT. Because she had failed prior standard measures, 4 weekly infusions of rituximab (375 mg/m2) were given following 2 rounds of plasmapheresis. Subsequently, she made a remarkable recovery over the next month and has been free of thrombosis on Coumadin for over 15 months. LA, IgM antibodies to cardiolipin, and B2GP1 were consistently positive. After rituximab therapy, LA became negative and IgM antibodies to cardiolipin decreased and ITP went into remission. Rituximab induced a lasting remission in a woman suffering from life-threatening hypercoagulable state associated with LA. Her clinical remission was associated with disappearance of LA.

Effects of inherited thrombophilic mutations in an adolescent with antiphospholipid syndrome and systemic lupus erythematosus.

Thrombophilia can result from either inherited or acquired conditions. We describe a teenager who developed extensive thrombosis requiring aggressive and prolonged anticoagulation. Laboratory evaluation revealed an acquired lupus anticoagulant, consistent with the antiphospholipid antibody syndrome (APS). DNA analysis revealed inherited thrombophilic mutations in the factor V and methylene tetrahydrofolate reductase genes. We believe that the combination of inherited and acquired hypercoagulable conditions affected her therapeutic response to anticoagulant therapy. Inherited thrombophilic DNA mutations may contribute to the hypercoagulability observed in patients with acquired thrombophilic conditions such as APS and systemic lupus erythematosus.

An improved test to identify aPC-resistant factor V-Leiden.

A functional clotting assay was recently reported to detect the factor V-Leiden mutation (R506Q) in patients receiving oral anticoagulants and in patients with Lupus Anticoagulant inhibitor. The original assay (Dahlback) to detect resistance to activated protein C (aPC-resistance) frequently gave unreliable findings in these patients. The change in the method is the use of bovine thromboplastin in a PT-derived assay, with a 1:10 sample dilution. In these conditions a reference normal plasma gives a prolongation of more than 35 seconds, while samples with a heterozygous or homozygous mutation give a prolongation respectively of 10-18 seconds or less 2 seconds. The test is easily automated and quickly performed on ACL/3000, and the reproducibility is good.

Effects of two combined monophasic and triphasic ethinylestradiol/gestodene oral contraceptives on natural inhibitors and other hemostatic variables.

OBJECTIVE: To evaluate the effects of two preparations of combined oral contraceptives (COCs), the monophasic COC containing 30 micrograms ethinylestradiol and 75 micrograms gestodene and the triphasic COC containing 30/40/30 ethinylestradiol and 50/70/100 micrograms gestodene on seven natural inhibitors and hemostatic variables. METHOD: Forty-four healthy young women, randomly allocated into two groups (A and B) received the two preparations of COCs, respectively. The following variables were tested in a basic examination and at 1-, 3- and 6-month intervals to evaluate the role of the above preparations on the hemostatic balance of prothrombin time, fibrinogen, antithrombin III activity, protein C activity, total protein S antigen, plasminogen activity and lupus anticoagulant. RESULTS: Group A women presented shorter prothrombin time at 6 months, an increased fibrinogen level at 3 months, no influence on the anticoagulant factors, antithrombin III, protein C and total protein S and an increased plasminogen activity at the 1st and 3rd months of treatment. On the other hand, group B women presented shorter prothrombin time at 3 months, no increase in fibrinogen, a decrease in antithrombin III activity and total protein S activity at the 6th month, whereas protein C and plasminogen activities were found to be increased at the 3rd and 1st, 3rd and 6th month, respectively. CONCLUSIONS: The study did not find differences between the two treatment groups, for the evaluated parameters. This finding is clearly important in the light of the recent epidemiological reports on third-generation COCs. However, differences were found among the various periods of administration of both COCs.

Tratamiento del factor inmunológico en el aborto recurrente y en el retardo de crecimiento intrauterino / Treatment of the immunologic factor in the recurrent abortion and the intrauterine growth retardation

Objetivo: Describir los resultados del tratamiento anti-agregante plaquetario en un grupo de pacientes con auto-anticuerpos y antecedentes de aborto recurrente (AR) y/o retardo de crecimiento intrauterino (RCIU). Material y Método: Catorce pacientes que consultaron por AR y/o RCIU, en cuyo estudio inmunológico se detectaron autoanticuerpos, constituyen el material del presente trabajo. A las pacientes que tenían como antecedentes un RCIU, una vez descartados todos los cuadros clínicos que pudieran ocasionarlo, se les efectuó determinación de autoanticuerpos. Las parejas que consultaban por AR eran sometidas a estudio para descartar un factor uterino, infeccioso, endocrinológico, metabólico, genético, inmunológico y espermático. En algunas pacientes se realizó una laparoscopia para descartar endometriosis. Todas las pacientes fueron tratadas con Acido Acetilsalicílico (AAS) 80 mg. diarios, a partir del momento de la detección de autoanticuerpos. A una sola paciente se le administró además Heparina subcutánea durante dos embarazos. Resultados: De las catorce pacientes en las que se detectaron autoanticuerpos, doce embarazaron, algunas de ellas en más de una oportunidad, sumando un total de 19 embarazos. De ellos, 5 concluyeron en aborto espontáneo y catorce concluyeron en el tercer trimestre con recién nacido vivo. De éstos, cinco presentaron un crecimiento fetal normal, mientras que los nueve restantes desarrollaron RCIU. La vía de terminación fue vaginal en cinco casos y abdominal en los nueve restantes. Conclusiones: El tratamiento del síndrome antifosfolipídico con antiagregantes plaquetarios (AAS o heparina), parecería ofrecer un porvenir reproductivo alentador a las portadoras de dicho síndrome (AU)

ARACHnase. An evaluation of a positive control for platelet neutralization procedure testing with seven commercial activated partial thromboplastin time reagents.

ARACHnase (Hemostasis Diagnostics International Co., Denver, CO) is a normal plasma that contains a venom extract from the brown recluse spider, Loxosceles reclusa, which mimics the presence of a lupus anticoagulant (LA). Seven activated partial thromboplastin time (APTT) reagents were used for platelet neutralization procedure (PNP) testing with ARACHnase: Automated APTT (Organon-Teknika, Durham, NC); Thrombofax and Thrombosil (Ortho, Raritan, NJ); Actin and Actin FSL (Dade, Aguado, PR); and Thromboscreen-Kontact and Thromboscreen-APTT LS (Pacific-Hemostasis, Ventura, CA). ARACHnase consistently displayed a positive PNP result of greater than 5 seconds correction of the initial baseline APTT. Thus, ARACHnase may provide a positive control for LA testing, regardless of the choice of APTT reagent and activator/phospholipid combination.