Diferencias en la conclusión final de la búsqueda de anticoagulante lúpico en pacientes anticoagulados con antagonistas de la vitamina K / Differences in the final conclusion of the search for lupus anticoagulant in patients anticoagulated with vitamin K antagonists

Resumen Introducción. La detección de anticoagulante lúpico (AL) en pacientes que reciben el tratamiento con antagonistas de la vitamina K (AVK) es todavía una asignatura pendiente. Algunas guías recomiendan realizar todas las pruebas en la mezcla equimolar del plasma del paciente y el pool de plasmas normales (PN+PP), en aquellos pacientes con RIN<3. Sin embargo, la última guía de la ISTH sugiere no determinar AL en pacientes con AVK. Objetivo. Comparar la conclusión final de los estudios de AL, realizando las pruebas de tamizaje y confirmatorias en el plasma puro (PP) y en la mezcla (PP+PN), en pacientes en tratamiento con AVK. Población. 90 pacientes con diagnóstico previo de AL persistente, que al momento de su inclusión estaban en tratamiento con AVK con RIN < 3. Todos habían sido estudiados por segunda vez para confirmar el diagnóstico de AL persistente, a los tres meses, bajo tratamiento anticoagulante con heparina de bajo peso molecular y luego continuaron con el tratamiento con AVK. Materiales y métodos. Se realizaron los ensayos de tamizaje y confirmatorio del tiempo de veneno de víbora de Russell (dRVVT y cRVVT) y del tiempo de coagulación de sílice (sSCT y cSCT). Se preparó el pool de plasmas normales con 40 donantes de sangre, que fueron negativos para la evaluación de AL. Los puntos de corte fueron establecidos localmente de acuerdo a la guía ISTH. Resultados. 33/90 pacientes fueron AL positivo tanto en PP como en PP+PN, 27 negativos y 30 discordantes. 46 de las 90 muestras fueron positivas por dRVVT en PP, pero sólo 18/90 fueron positivas por ensayo de dRVVT en PP+PN. El valor de kappa para la medida de la concordancia entre el ensayo dRVVT en ambas situaciones fue de 0,21 (IC del 95 % = 0,047-0,374). 52/90 fueron negativos por ensayo SCT en PP y 50/90 fueron negativos en PP+PN. 31/90 fueron positivos en ambos casos. Sólo 9/90 fueron positivos por SCT en PP+PN y negativos en PP. El índice kappa para el SCT fue 0,64 (0,431-0,844). Discusión. Aunque realizar las pruebas de AL en PP+PN en pacientes anticoagulados con AVK es una práctica habitual, de acuerdo con estos resultados no es una buena opción, porque podría dar un diagnóstico falsamente negativo o positivo, dependiendo del ensayo. La discrepancia entre usar o no la mezcla es mayor en el ensayo de Drvvt.

Abstract Introduction. The detection of lupus anticoagulant (LA) in patients who are on vitamin K antagonist (VKA) treatment is still an unresolved issue. Some guidelines recommend performing all tests on the equimolar mixture of the patient's plasma plus normal plasma pool (PN+PP) in those patients with INR<3. However, the latest ISTH guideline suggests not determining LA in patients with VKA. AIM. To compare the final conclusion of LA studies, performing screening and confirmatory tests in pure plasma (PP) and in the mixture (PP+PN), in patients receiving VKA treatment. Population. 90 patients with a previous diagnosis of persistent AL, who at the time of inclusion were in treatment with VKA with INR < 3. All had been studied for a second time to confirm the diagnosis of persistent LA, three months later, under anticoagulant treatment with low molecular weight heparin and then continued treatment with VKA. Materials and methods. Screening and confirmatory tests of Russell's viper venom time (dRVVT and cRVVT) and silica coagulation time (sSCT and cSCT) were performed. The normal plasma pool was prepared with 40 blood donors, who were negative for the AL evaluation. The cut-off points were established locally according to the ISTH guideline. Results. 33/90 patients were LA positive considering PP and PP+PN, 27 were negative and 30 discordant. 46 of the 90 samples were positive by dRVVT in PP but only 18/90 were positive by dRVVT assay in PP+PN. The kappa value for the measure of agreement between the dRVVT test in both situations was 0.21 (95% CI = 0.047-0.374). 52/90 were negative by SCT assay in PP and 50/90 were positive in PP+PN. Only 9/90 were positive by SCT in PP+PN and negative in PP. The kappa index for the SCT was 0.638 (0.431-0.844). Discussion. Although performing LA tests on the PP+PN mixture in anticoagulated patients with VKA is a common practice, according to these results, it is not a good option because they could give a false negative or positive diagnosis, depending on the assay. The discrepancy between using or not using the mixture is greater in dRVVT´s assay.

A mysterious hematochezia in an adolescent boy: atypical presentation of childhood systemic lupus erythematosus

Thrombosis is a well-known entity in presence of antiphospholipid antibody (APLA) associated with systemic lupus erythematosus (SLE) as a hematological complication. Bleeding manifestations instead of thrombosis is hardly found in literature in presence of APLA seromarkers in SLE. Since these can range from minor bleeding like epistaxis to major life-threatening intracranial bleeding, early diagnosis and prompt treatment is essential to manage such condition. We report a 12 years old boy with no significant past history presented with hematochezia and epistaxis along with pallor requiring blood transfusion. Hematological investigations were normal except for elevated PT, aPTT and INR. Common causes of coagulopathy were ruled out. Upon suspecting systemic diseases, the investigations were carried out which revealed ANA 4+ along with high titre of dsDNA, low C3 and C4 complement and positive anti-?2 glycoprotein, anticardiolipin antibody and lupus anticoagulant. Diagnosis of SLE was made according to ACR-EULAR criteria with no renal involvement. Immunological basis was considered for coagulopathy in this child. He was started on oral prednisolone, hydroxychloroquine and methotrexate. He is now under close monitoring of the coagulation profile for titration of steroid dose. We want to create awareness about the uncommon hematological manifestation of SLE presenting as bleeding diathesis instead of thrombosis through this case report and that can be life threatening too if not treated promptly. A high index of suspicion and careful follow-up may help in preventing adverse outcome of the disease.

Lupus anticoagulant-hypoprothrombinemia syndrome associated with systemic lupus erythematosus / Síndrome de LAHS asociado a lupus eritematoso sistêmico

Abstract Introduction: thromboembolic phenomena are among the most common hematologic mani festations in patients with systemic lupus erythematosus (SLE) who have lupus anticoagulant, while hemorrhagic events are less frequent and tend to occur with Factor II deficiency. Lupus anticoagulant-hypoprothrombinemia syndrome (LAHS) is a rare disorder and its association with SLE is uncommon, especially in adults. Case presentation: we present the case of a 19-year-old male patient diagnosed with LAHS associated with SLE, with kidney and skin involvement evidenced by lower extremity purpura and hematuria. Treatment was begun early with corticosteroid pulses, cyclophosphamide and mycophenolate mofetil, with an adequate clinical response. Conclusion: understanding the association between LAHS and SLE helps providers suspect this condition in patients with acquired coagulation disorders and recognize it as the initial manifestation of an underlying systemic disease. Early diagnosis and prompt treatment reduce mortality in these patients. (Acta Med Colomb 2022; 48. DOI:https://doi.org/10.36104/amc.2023.2745).

Resumen Introducción: los fenómenos tromboembólicos hacen parte de las manifestaciones hematológicas más comunes de los pacientes con lupus eritematoso sistémico (LES) que presentan anticoagulante lúpico, mientras que los eventos hemorrágicos son menos frecuentes y suelen manifestarse en pre sencia de deficiencia de factor II. El síndrome de LAHS es una afección rara y su asociación con LES es infrecuente, especialmente en etapa adulta. Presentación del caso: se presenta el caso de un paciente masculino de 19 años diagnosticado con síndrome de LAHS asociado a LES con compromiso renal y cutáneo manifestado por púrpuras en extremidades inferiores y hematuria. Se instauró tratamiento con pulsos de corticoides, ciclofosfamida y micofenolato mofetil de forma temprana observándose una adecuada respuesta clínica. Conclusión: conocer la asociación entre el síndrome de LAHS y LES permite sospechar esta entidad en pacientes con trastornos adquiridos de la coagulación y reconocerla como manifestación inicial de una enfermedad sistémica subyacente. El diagnóstico temprano y tratamiento oportuno reduce la mortalidad en estos pacientes. (Acta Med Colomb 2022; 48. DOI:https://doi.org/10.36104/amc.2023.2745).

Hypoprothrombinemia-lupus anticoagulant syndrome secondary to Sjogren's syndrome:A case report / 中南大学学报(医学版)

Hypoprothrombinemia-lupus anticoagulant syndrome(HLAS)is a rare disease in which patients present with varying degrees of bleeding and positive lupus anticoagulant with reduced prothrombin on laboratory tests.This article reports a case of HLAS in a middle-aged woman with recurrent gingival bleeding and epistaxis as the first presentation.After admission,tests revealed prolonged prothrombin time(PT),activated partial thromboplastin time(APTT),and reduced coagulation factor Ⅱ activity,and positive lupus anticoagulant(LA).Meanwhile,the patient had symptoms of dry mouth and dry eyes for a long time,and the examination of autoantibodies,tear secretion test and salivary gland emission computed tomography(ECT)were consistent with the diagnosis of Sjogren's syndrome.The final diagnosis was HLAS secondary to Sjogren's syndrome.After treatment with methylprednisolone and cyclophosphamide,the coagulation disorder gradually improved,and no recurrent bleeding occurred.HLAS is a rare clinical case,which reminds medical staff to be alert to the possibility of HLAS when encountering patients with unexplained prolonged APTT and PT and positive lupus anticoagulant.

COVID-19 coagulopathy and antiphospholipid syndrome

The presence of thrombotic events in COVID-19 patients has been described since the beginning of the pandemic. This association has been confirmed in most of the reported studies. Autopsy reports have shown that most thromboses are located in the lung, although they have also been observed in other organs such as the skin and kidneys. SARS-CoV2 infection induces a generalized prothrombotic state, which is attributed to a combination of factors such as hypoxia, excess cellular apoptosis, and mainly to overactivation of the immune system. Among immune-mediated prothrombotic situations, antiphospholipid syndrome (APS) stands out. Recurrent thrombotic events are observed in APS in the presence of antiphospholipid antibodies (aPL). There are numerous studies that report high prevalence of aPL in patients with COVID-19 infection. However, the results show discrepancies in the data on the prevalence of aPL, and its role in the pathogenesis of thrombosis in these patients. This could be due to the heterogeneity of the detection procedures for aPL or to transient elevations of non-pathogenic aPL levels in the context of infection. In this review we try to clarify the role of aPL in COVID-19 infection, and attempt to answer the question of whether it is a coagulopathy of its own, or secondary to APS.

La presencia de eventos trombóticos en los pacientes con COVID-19 se describió desde el inicio de la pandemia, asociación que ha sido confirmada en la mayoría de los estudios reportados. Los informes de necropsias han puesto de manifiesto que la mayoría de las trombosis se localiza en el pulmón, aunque también se han observado en otros órganos, como la piel y los riñones. La infección por SARS-CoV-2 induce un estado protrombótico generalizado que se atribuye a una conjunción de factores como la hipoxia, el exceso de apoptosis celular y, sobre todo, una hiperactivación del sistema inmune. Entre las situaciones protrombóticas inmunomediadas destaca el síndrome antifosfolipídico, en el cual se observan eventos trombóticos de repetición en presencia de anticuerpos antifosfolipídicos (AAF). Existen numerosos estudios que reportan una elevada prevalencia de AAF en los pacientes con infección por la COVID-19; sin embargo, los resultados muestran discordancias en los datos de prevalencia de AAF y su rol en la patogenia sobre la trombosis en estos pacientes, lo que que podría deberse a la heterogeneidad de los procedimientos de detección de los AAF o a elevaciones transitorias de los niveles de AAF no patogénicos en el contexto de la infección. En esta revisión se busca aclarar el papel de los AAF en la infección por COVID-19, intentando responder a la pregunta de si se trata de una coagulopatía propia o es secundaria a un síndrome antifosfolipídico.

The Changes of Peripheral Blood FⅫa-AT, TSP-1, LA Ratio in Patients with Systemic Lupus Erythematosus and the Clinical Value of Combined Diagnosis of Thrombotic Events / 中国实验血液学杂志

OBJECTIVE@#To explore the changes of Ⅻ antithrombin (FⅫa-AT), thrombospondin-1 (TSP-1), and lupus anticoagulant (LA) ratio in the peripheral blood factor of patients with systemic lupus erythematosus (SLE) and the clinical value of combined diagnosis of thrombotic events.@*METHODS@#A total of 133 SLE patients treated in Xingtai People's Hospital were selected and divided into simple SLE group (105 cases) and SLE complicated with thrombosis group (28 cases) according to whether thrombotic events occurred, and 102 cases of healthy people in the same period were selected as control. The clinical data of the 3 groups, the level of peripheral blood FⅫa-AT, TSP-1, and LA ratio were compared, the relationship between each peripheral blood index and SLE disease activity index (SLEDAI) score were analyzed. The influencing factors of thrombotic events in SLE patients were analyzed, and the value of each peripheral blood index in the diagnosis of SLE complicated with thrombotic events were evaluated.@*RESULTS@#The proportion of the patients with age ≥60 year, hypertension, and smoking history in SLE complicated with thrombosis group was higher than those in simple SLE group and control group (P＜0.05). The SLEDAI score, peripheral blood FⅫa-AT, TSP-1, LA ratio levels of the patients in SLE complicated with thrombosis group were significantly higher than those in simple SLE group and control group, and the simple SLE group was significantly higher than the control group (P＜0.05). FⅫa-AT, TSP-1, LA ratio in peripheral blood of SLE patients were positively correlated with SLEDAI score (r=0.663, 0.578 and 0.625). Age, blood pressure, smoking history, peripheral blood FⅫa-AT, TSP-1, LA ratio were the important influencing factors of thrombotic events in SLE patients (P＜0.05). The AUC diagnosed by the FⅫa-AT, TSP-1, and LA ratio in peripheral blood was 0.881, the 95% CI was 0.813-0.931, the sensitivity was 82.14%, and the specificity was 91.43%, which was superior to each index alone (P＜0.05).@*CONCLUSION@#Peripheral blood FⅫa-AT, TSP-1, LA ratio level changes in SLE patients are significantly related to disease activity, and the combined diagnosis of thrombotic events is more reliable.

Clinical characteristics and risk factors of ischemic stroke in young adults / 中国综合临床

Objective:To analyze the clinical characteristics and risk factors of ischemic stroke in young adults.Methods:A retrospective analysis was conducted on 80 ischemic stroke patients (age ≤45 years) admitted to Beijing Tiantan Hospital from March 2019 to October 2019 as the young stroke group, and 117 ischemic stroke patients (age >45 years) hospitalized during the same period as the middle-aged and elderly stroke group. The blood test indexes of the two groups were compared, and the risk factors related to stroke, including smoking history, drinking history, hypertension, hyperlipidemia and diabetes history, were compared and analyzed. Two sets of independent sample t-test, Mann-Whitney U-test or χ2 test were used to compare the above indicators of patients in the two groups. Results:The activated partial prothrombin time, protein S, uric acid, homocysteine and D-dimer levels in middle-aged and elderly stroke group were (29.73±3.40) s, (105.58±27.23) %, (297.29±85.99) μmol/L, (17.58±14.45) μmol/L and (2.75±3.08) mg/L, respectively. Compared with the middle-aged and elderly stroke group, the young stroke group had higher activated partial thrombin time (31.51±6.75) s, protein S (115.20±26.97) %, uric acid (326.82±93.51) μmol/L, homocysteine (22.63±16.98) μmol/L and lower D dimer level of (1.19±2.88) mg/L compared with the elder group, the difference between the two groups was statistically significant ( t values were 2.17, 2.01, 2.20, 2.14 and 2.13, respectively, P values were 0.032, 0.046, 0.029, 0.039 and 0.034, respectively). The positive rate of lupus anticoagulant in young stroke group was 12.5% (4/32), which was higher than 1.8% (1/57) in middle-aged and elderly stroke group, and there was significant difference between the two groups (χ 2=4.46, P=0.035). The proportions of smoking and drinking in young stroke group were 63.8% (51/80) and 62.5% (50/80), respectively, which were higher than 49.6% (58/117) and 47.9% (56/117) in middle-aged and elderly stroke group, and there was significant difference between the two groups (χ 2 values were 3.86 and 4.09; P values were 0.04 and 0.04). The proportion of hypertension and diabetes in young stroke group was 48.8% (39/80) and 17.5%(14/80), respectively, which were lower than 63.2%(74/117) and 30.8%(36/117) in middle-aged and elderly stroke group, and there was significant difference between the two groups (χ 2 values were 4.08 and 4.56; P values were 0.043 and 0.033). According to the levels of uric acid and homocysteine, young stroke was divided into different subgroups and compared.The creatinine level of high uric acid group (≥416 μmol/L) was (90.08±28.46) mmol/L, which was higher than that of normal uric acid group (<416 μmol/L) of (63.37±22.2) mmol/L. There was significant difference between the two groups ( t value was 2.23, P value was 0.046). The levels of fibrinogen and creatinine in high homocysteine group (≥15 μmol/L) were (3.27±1.09) g/L and (72.13±28.69) mmol/L, respectively which were significantly higher than those in normal homocysteine group (<15 μmol/L) of (2.78±0.67) g/L and (58.92±12.08) mmol/L, There was significant difference between the two groups (the t values were 2.32 and 2.51; P values were 0.023 and 0.014). Conclusions:Compared with middle-aged and elderly stroke, young ischemic stroke has higher levels of prothrombin time, protein S, uric acid and homocysteine, lower levels of D dimer and higher positive rate of lupus anticoagulant. At the same time, the proportion of smoking and drinking was higher in young stroke group, but the proportion of hypertension and diabetes was relatively lower.

Recurrent epistaxis with coagulation disorders in a boy aged 2 years / 中国当代儿科杂志

A boy, aged 2 years and 5 months, had recurrent epistaxis, and the coagulation function examination showed that activated partial thromboplastin time (APTT) was significantly prolonged. Further laboratory examinations showed that the prolonged APTT was not immediately corrected in the APTT correction test, with positive lupus anticoagulant and low prothrombin activity. The boy was diagnosed with hypoprothrombinemia-lupus anticoagulant syndrome. The condition was improved after treatment with glucocorticoid, immunoglobulin, and vitamin K1. The boy has been followed up for 6 months, and no epistaxis was observed. Prothrombin activity returned to normal, and lupus anticoagulant remained positive. This is a relatively rare disease, and for patients with bleeding symptoms and coagulation disorders, it is recommended to perform the tests such as APTT correction test, lupus anticoagulant testing, and coagulation factor dilution test, which can improve the detection rate of this disease, so as to achieve early diagnosis, provide rational treatment in the early stage, and improve the prognosis.

Laboratory examination and clinical characteristics of patients with ischemic stroke of positive lupus anticoagulant / 中国综合临床

Objective:To analyze the laboratory tests and clinical characteristics of patients with lupus anticoagulant-positive cerebral infarction.Methods:A retrospective analysis of 216 patients with cerebral infarction hospitalized in Beijing Tiantan Hospital from January 2016 to October 2021 was performed, and the patients were divided into LA-positive cerebral infarction group (168 cases) and LA-negative cerebral infarction group (48 cases) according to the detection of lupus anticoagulant (LA) in cerebral infarction patients, and the laboratory test data between the two groups were compared, and the risk factors related to cerebral infarction, including body mass index (BMI), smoking history, drinking history, hypertension, hyperlipidemia, diabetes history, were included for comparative analysis. LA was performed using the silica clotting time (SCT) method and the modified diluted russell viper venom time (dRVVT) method, respectively. The dRVVT method was used to detect LA. The LA-positive cerebral infarction group was divided into three subgroups according to the positive detection, namely, the dRVVT single-positive group (110 cases), the SCT single-positive group (40 cases) and the double-positive group (18 cases), and the comparison of laboratory indices between different subgroups was performed.The measurement data of normal distribution between the two groups were compared by independent sample t-test, and the mean between multiple groups was compared by ANOVA; The rank sum test was used to compare the median between the measurement data groups that did not conform to the normal distribution, and the χ 2 test was used to compare the counting data groups. Results:The levels of antithrombin Ⅲ and protein C of the LA-positive group ((102.85±14.39)% and (108.52±22.62)%) were all lower than those of the LA-negative group ((110.16±11.10)% and (116.34±18.14)%), the difference was statistically significant ( t values were 3.25, 2.20, P values were 0.001, 0.029, respectively). The levels of fibrinogen, homocysteine, high-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate, white blood cells and neutrophil were (3.43(3.07,4.03) g/L), (17.92(14.07,23.71) μmol/L), (6.97(2.33,11.46) mg/L), (15.00(6.75,29.00) mm/h), (8.61(6.72,10.86)×10 9/L) and (5.81(4.39,7.91)×10 9/L), all were higher than those in the LA-negative group with values of (3.14(2.68, 3.62) g/L), (14.62(12.49, 18.41) μmol/L), (3.18(2.09,4.32) mg/L), (9.50(3.75,19.00) mm/h), (7.20(6.22,8.33)×10 9/L) and (4.47(4.02,5.57)×10 9/L), and the differences were statistically significant ( Z values were 2.77, 2.89, 3.32, 2.45, 3.15 and 3.76, P values were 0.006、0.004、0.001, 0.014, 0.002 and <0.001, respectively). There were no significant differences in age, gender, BMI, personal history, past medical history and other laboratory indicators between the two groups (all P>0.05). Comparison among different subgroups in LA positive group showed that D dimer and hs-CRP levels in double-positive group were 0.58(0.50,0.84) mg/L and 7.77(5.94,21.61) mg/L, higher than those in SCT single-positive group with values of 0.45(0.32,0.56) mg/L and 2.98(1.09,6.07) mg/L, and protein S level of double-positive group (97.36±25.45)% was lower than that in SCT single-positive group (114.85±22.74)%, the differences were statistically significant (all P<0.05). D dimer, prothrombin time, hs-CRP and neutrophil levels in dRVVT single-positive group were (0.58(0.50,0.84) mg/L), (11.40(11.10,12.10) s), (6.97(4.07,11.97) mg/L) and (5.83(4.51,8.27)×10 9/L), which were higher than those in SCT single-positive group with values of (0.45(0.32,0.56) mg/L), (11.15(10.70,11.43) s), (2.98(1.09,6.07) mg/L) and (5.08(3.92,6.07)×10 9/L), the difference was statistically significant (all P<0.05). Protein C and triglyceride levels were ((105.65±20.62)%) and (1.38(1.05, 1.75) mmol/L) in dRVVT single-positive group, which were lower than those in SCT single-positive group with values of ((117.05±20.86)% and 1.60(1.29,2.36) mmol/L), the differences were statistically significant (all P<0.05). Conclusion:There were significant differences between LA positive and LA negative cerebral infarction patients in laboratory examination. In LA positive cerebral infarction patients, the levels of fibrinogen, homocysteine, hs-CRP, white blood cells, neutrophil and erythrocyte sedimentation rate were higher, while the levels of anticoagulant protein antithrombin Ⅲ and protein C were lower. It is of great significance to pay close attention to the level and change of laboratory related risk factors in patients with LA positive cerebral infarction and give early intervention and treatment for the prevention of the occurrence and recurrence of cerebral infarction.

The antiphospholipid syndrome / El síndrome antifosfolipídico

ABSTRACT APS is a hypercoagulability condition characterized by the development of thrombosis and pregnancy morbidity (recurrent early miscarriages, fetal deaths after the 10th week of gestation and/or premature births), that occur in patients with antiphospholipid antibodies, namely lupus anticoagulant, anticardiolipin antibodies, and anti-(32-glycoprotein-I antibodies. It is usually isolated but can occur in the setting of another autoimmune disease, mainly systemic lupus erythematosus. Moreover antiphospholipid antibodies can be found in individuals without the disease. Treatment of thrombosis is based on indefinite anticoagulation while low-dose aspirin and low molecular weight heparin are the cornerstone of pregnancy morbidity treatment. Catastrophic antiphospholipid syndrome is treated with anticoagulation, plasma-exchange, and corticosteroids. Standardization of serological assays, inclusion of other antibodies and manifestations in the classification criteria, treatment of non-criteria manifestations and refractory cases are areas of uncertainty.

RESUMEN El SAF es una condición de hipercoagulabilidad caracterizada por el desarrollo de trombosis y morbilidad obstétrica (abortos recurrentes, muertes fetales antes de la semana 10 de gestación y/o partos prematuros) en pacientes con anticuerpos antifosfolipídicos, específicamente el anticoagulante lúpico, los anticuerpos anticardiolipina y anti-(32-glicoproteína-1. En la mayoría de los casos se presenta de forma aislada, pero puede asociarse a otras enfermedades autoinmunes como el lupus eritematoso sistêmico. Además, los anticuerpos antifosfolipídicos se pueden encontrar en individuos sin la enfermedad. El tratamiento de la trombosis se basa en anticoagulación indefinida, mientras que aspirina a dosis bajas y heparina de bajo peso molecular representan la base del tratamiento de la morbilidad obstétrica. El síndrome de anticuerpos antifosfolipídicos catastrófico se trata con una combinación de anticoagulación, corticoides y recambios plasmáticos. La estandarización de los ensayos serológicos, la inclusión de otros anticuerpos y otras manifestaciones en los criterios clasificatorios, el tratamiento de las manifestaciones no criterio y de los casos refractarios representan las áreas de incertidumbre del síndrome.

Clinical and laboratory characteristics of Brazilian versus non-Brazilian primary antiphospholipid syndrome patients in AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) clinical database and repository

Abstract Background: Antiphospholipid syndrome (APS) is characterized by episodes of thrombosis, obstetric morbidity or both, associated with persistently positive antiphospholipid antibodies (aPL). Studying the profile of a rare disease in an admixed population is important as it can provide new insights for understanding an autoimmune disease. In this sense of miscegenation, Brazil is characterized by one of the most heterogeneous populations in the world, which is the result of five centuries of interethnic crosses of people from three continents. The objective of this study was to compare the clinical and laboratory characteristics of Brazilian vs. non-Brazilian primary antiphospholipid syndrome (PAPS) patients. Methods: We classified PAPS patients into 2 groups: Brazilian PAPS patients (BPAPS) and PAPS patients from other countries (non-BPAPS). They were compared regarding demographic characteristics, criteria and non-criteria APS manifestations, antiphospholipid antibody (aPL) profile, and the adjusted Global Antiphospholipid Syndrome Score (aGAPSS). Results: We included 415 PAPS patients (88 [21%] BPAPS and 327 [79%] non-BPAPS). Brazilian patients were significantly younger, more frequently female, sedentary, obese, non-white, and had a higher frequency of livedo (25% vs. 10%, p < 0.001), cognitive dysfunction (21% vs. 8%, p = 0.001) and seizures (16% vs. 7%, p = 0.007), and a lower frequency of thrombocytopenia (9% vs. 18%, p = 0.037). Additionally, they were more frequently positive for lupus anticoagulant (87.5% vs. 74.6%, p = 0.01), and less frequently positive to anticardiolipin (46.6% vs. 73.7%, p < 0.001) and anti-ß2-glycoprotein-I (13.6% vs. 62.7%, p < 0.001) antibodies. Triple aPL positivity was also less frequent (8% vs. 41.6%, p < 0.001) in Brazilian patients. Median aGAPSS was lower in the Brazilian group (8 vs. 10, p < 0.0001). In the multivariate analysis, BPAPS patients still presented more frequently with livedo, cognitive dysfunction and sedentary lifestyle, and less frequently with thrombocytopenia and triple positivity to aPL. They were also less often white. Conclusions: Our study suggests a specific profile of PAPS in Brazil with higher frequency of selected non-criteria manifestations and lupus anticoagulant positivity. Lupus anticoagulant (not triple positivity) was the major aPL predictor of a classification criteria event.

Practice and performance of lupus anticoagulant tests: A single centre experience

@#Introduction: Lupus anticoagulant (LA) is a well-known risk factor for thrombosis. Correct diagnosis of LA is essential in patient management with anticoagulation. The objectives of this study were to document the clinical and laboratory characteristics of patients tested for LA and to evaluate existing LA testing methods in our laboratory with the aim of improving the performance of LA test interpretation and reporting. Methods: Tests for LA include dilute Russell’s viper venom time (dRVVT) and Kaolin clotting time (KCT). Patients with LA ratio (dRVVT screen ratio/dRVVT confirm ratio) of ≥1.2 were considered as LA positive irrespective of KCT results. KCT was considered positive if there was a prolongation in KCT screening test which was not corrected on mixing with normal plasma. Results: Of 577 patients’ results, 295 were normal, 178 were KCT positive with negative dRVVT and 104 were LA positive. Incidences of thrombosis, connective tissue disease (CTD) and bad obstetric events were noted in 13%, 16% and 44% of normal patients, 9%, 22% and 49% of KCT+ patients and 23%, 37% and 17% of LA+ patients respectively. On further evaluation of dRVVT screen ratios, 431 had a ratio of <1.1, 59 had a ratio between 1.1 and 1.2 and 87 had a ratio of >1.2. Positive LA results were found in 3%, 29% and 87% of patients with dRVVT screen ratios of <1.1, 1.1 - 1.2 and >1.2 respectively. Conclusion: LA+ patients had higher incidences of thrombosis and CTD as compared to normal and KCT only positive patients. There was no significant difference in clinical characteristics between normal and KCT+ patients which suggests the presence of a high rate of false-positive KCT results. Since confirmatory testing for KCT is not widely used, the option of using another LA screening test method should be considered. In regard to dRVVT testing, confirmatory test should only be performed in patients with prolonged dRVVT screening result which was not corrected upon mixing with normal plasma as required by the International Society of Thrombosis and Haemostasis guidelines on LA testing. This practice will not only result in significant cost reduction but also avoid diagnostic confusion.

Utilización de un dispositivo portátil para monitorear la relación internacional normalizada en pacientes con anticoagulante lúpico positivo / Use of a portable device to monitor the international normalized ratio in patients with positive lupus anticoagulant

La certeza del valor de la relación internacional normalizada (RIN), ensayo para controlar la anticoagulación con dicumarínicos, en pacientes con anticoagulante lúpico positivo (AL) es desconocida especialmente para los dispositivos al lado del paciente (POCT). El objetivo de este trabajo fue investigar si existe correlación entre el valor del RIN obtenido por el método tradicional y el obtenido con un dispositivo portátil en pacientes con AL positivo. Se estudiaron 35 pacientes anticoagulados por enfermedad tromboembólica con diagnóstico de AL positivo persistente a los que se les determinó al mismo tiempo el RIN por el método tradicional y con CoaguChek durante 4 controles consecutivos. El rango del RIN fue 1,9 a 5,60 y el RIN-POCT estuvo entre 2,0 y 4,92. La comparación del RIN vs RIN-POCT mostró r=0,98, pendiente: 1,56 (0,98-1,12) y una ordenada al origen de -0,088 (-0,282-0,007). El sesgo fue 2,1%. Para un nivel del RIN menor de 3,5 (n=136 controles) la diferencia del RIN promedio fue de 0,17 con un rango de 0,01-0,56. Un paciente, con triple positividad, mostró una diferencia entre ambos métodos mayor de 0,4 en dos controles. Para un RIN mayor de 4,5 el grado de concordancia fue menor pero no tiene implicancia clínica. Los resultados del RIN obtenidos por CoaguChek en los pacientes estudiados con AL positivo son útiles para la práctica clínica. Los datos obtenidos demuestran que hay una buena correlación entre el RIN tradicional y el CoaguChek. Por la gran diversidad de los equipos POCT los resultados no son extrapolables a otros dispositivos. Dada la heterogeneidad de los anticuerpos antifosfolípidos, es recomendable probar en cada paciente si hay una buena concordancia entre el RIN tradicional y el RIN-POCT.

The certainty of the value of the international normalized relation (INR) assay to control dicoumarin anticoagulation in patients with positive lupus anticoagulant (LA) is unknown especially for the point of care testing (POCT). The aim of this work was to investigate if there was a correlation between the INR values obtained by the traditional method and those obtained with a POCT in patients with positive LA. The population under study were 35 patients anticoagulated by thromboembolic disease with a persistent positive LA, whose INR was determined at the same time by the traditional method and with CoaguChek during 4 consecutive controls. The INR range was 1.9 to 5.60 and the RIN-POCT was between 2.0-4.92. The comparison of INR vs. INR - POCT showed r=0.98, slope: 1.56 (0.98-1.12) and ordered to the origin -0.088 (-0.282-0.007). The bias was 2.1%. For an INR level lower than 3.5 (n=136 controls) the average INR difference was 0.17 with a range of 0.01-0.56. One patient, with triple positivity showed a difference between both methods greater than 0.4. in two controls. For INR greater than 4.5, the degree of concordance is lower but has no clinical implications. The data obtained show that there is a good correlation between the traditional INR and the CoaguChek. The results of INR obtained by CoaguChek in patients studied with positive LA are useful for clinical practice. Due to the large diversity of POCT, the results cannot be extrapolated to other devices. Given the heterogeneity of antiphospholipid antibodies, it is advisable to test in each patient whether there is a good agreement between the traditional INR and INR-POCT.

A certeza do valor da razão internacional normalizada (RIN ou IIN), ensaio que controla a anticoagulação com dicumarínicos, em pacientes com anticoagulante lúpico positivo (AL) é desconhecida especialmente para os dispositivos de teste do tipo point-of-care (POCT). Este trabalho teve como objetivo pesquisar se existe correlação entre o valor de RIN obtido pelo método tradicional e aquele obtido com um dispositivo portátil em pacientes com AL positivo. Foram estudados 35 pacientes anticoagulados por doença tromboembólica com diagnóstico de AL positivo persistente aos quais lhes determinaram, ao mesmo tempo, a RIN pelo método tradicional e com CoaguChek durante 4 controles consecutivos. O intervalo de RIN foi de 1,9 a 5,60 e o de RIN-POCT ficou entre 2,0 e 4,92. A comparação de RIN vs RIN-POCT mostrou r=0,98, pendente: 1,56 (0,98-1,12) e uma ordenada à origem de -0,088 (-0,282-0,007). O viés foi 2,1%. Para um nível de RIN menor a 3,5 (n=136 controles) a diferença de RIN em média foi de 0,17 com um intervalo de 0,01-0,56. Um paciente, com tríplice positividade, mostrou uma diferença entre ambos os métodos maior a 0,4 em dois controles. Para um RIN de mais de 4,5, o grau de concordância foi menor, mas não tem consequências clínicas. Nos pacientes estudados com AL positivo, os resultados da RIN obtidos por CoaguChek são úteis para a prática clínica. Os dados obtidos demonstram que existe uma boa correlação entre a RIN tradicional e o CoaguChek. Devido à grande diversidade dos equipamentos POCT, os resultados não são extrapoláveis a outros dispositivos. É recomendável, visto a heterogeneidade dos anticorpos antifosfolípídes, provar em cada paciente a existência de uma boa concordância entre a RIN tradicional e a RIN-POCT.

Evaluation of Rosners index vs Brandt correction and Chang’s %, in the interpretation of mixing studies at varying dilutions

Background: For evaluation of unexplained prolongation of PT and PTT, mixing tests forms a great diagnostic tool. On mixing equal volume of patient plasma with normal pooled plasma, if there is correction it indicates factor deficiency and non-correction indicates inhibitors.Methods: Sysmex CS-5100 Coagulometer with Pathrombin SL APTT reagent, LA1 and LA2 reagents supplied by siemens were used. All data were expressed as Mean±SD. Statistical analysis was done using unpaired students t test. A p value of <0.05 was used to indicate statistical significance in all analyse.Results: APTT with (1:1) and (4:1) mixing study for detection of factor deficiency showed a sensitivity of 91% and 92% for RI, 88% and 90% for Changs %, and 75% for Brandt correction PNP aPTT + 5 secs respectively. For Inhibitors, RI shows a sensitivity of 79% and 89%, Changs 71 and 80% and Brandt test 50% for APTT (1:1) and (4:1) mix, respectively.Conclusions: Mixing tests forms an important diagnostic tool in differentiating factor deficiency from inhibitors especially in LAC patients. This study recommends mandatory use of mixing tests in LAC cases as also advocated by BSH, ISTH and CLSI. Rosners Index is more sensitive than changes % and Brandt correction in the interpretation of mixing studies. It can be safely concluded that RI can be used as a reference method for evaluation of mixing studies and its sensitivity is greatly increased by using PP4:1 PNP. It’s a matter of debate that whether these indices can be effective with other Analysers and reagents?

Thrombophilia Caused by Beta2-Glycoprotein Ⅰ Deficiency: In Vitro Study of a Rare Mutation in APOH Gene / 华中科技大学学报（医学）（英德文版）

This study aimed to explore the mechanism of a novel mutation (p.Lys38Glu) in apolipoprotein H (APOH) gene causing hereditary beta2-glycoprotein Ⅰ (β2GPI) deficiency and thrombosis in a proband with thrombophilia.The plasma level of β2GPI was measured by ELISA and Western blotting,and anti-β2GPI antibody by ELISA.Lupus anticoagulant (LA) was assayed using the dilute Russell viper venom time.Deficiency of the major natural anticoagulants including protein C (PC),protein S (PS),antithrombin (AT) and thrombomodulin (TM) was excluded from the proband.A mutation analysis was performed by amplification and sequencing of the APOH gene.Wild type and mutant (c.112A＞G) APOH expression plasmids were constructed and transfected into HEK293T cells.The results showed that the thrombin generation capacity of the proband was higher than that of the other family members.Missense mutation p.Lys38Glu in APOH gene and LA coexisted in the proband.The mutation led to β2GPI deficiency and thrombosis by impairing the protein production and inhibiting the platelet aggregation.It was concluded that the recurrent thrombosis of the proband is associated with the coexistence ofp.Lys38Glu mutation in APOH gene and LA in plasma.

Thrombophilia Caused by Beta2-Glycoprotein Ⅰ Deficiency: In Vitro Study of a Rare Mutation in APOH Gene / 华中科技大学学报（医学）（英德文版）

This study aimed to explore the mechanism of a novel mutation (p.Lys38Glu) in apolipoprotein H (APOH) gene causing hereditary beta2-glycoprotein Ⅰ (β2GPI) deficiency and thrombosis in a proband with thrombophilia.The plasma level of β2GPI was measured by ELISA and Western blotting,and anti-β2GPI antibody by ELISA.Lupus anticoagulant (LA) was assayed using the dilute Russell viper venom time.Deficiency of the major natural anticoagulants including protein C (PC),protein S (PS),antithrombin (AT) and thrombomodulin (TM) was excluded from the proband.A mutation analysis was performed by amplification and sequencing of the APOH gene.Wild type and mutant (c.112A＞G) APOH expression plasmids were constructed and transfected into HEK293T cells.The results showed that the thrombin generation capacity of the proband was higher than that of the other family members.Missense mutation p.Lys38Glu in APOH gene and LA coexisted in the proband.The mutation led to β2GPI deficiency and thrombosis by impairing the protein production and inhibiting the platelet aggregation.It was concluded that the recurrent thrombosis of the proband is associated with the coexistence ofp.Lys38Glu mutation in APOH gene and LA in plasma.

Síndrome antifosfolípido catastrófico / Catastrophic antiphospholipid syndrome

El síndrome antifosfolípido está definido por la combinación de manifestaciones clínicas trombóticas y/u obstétricas y un título persistentemente alto y significativo de anticuerpos antifosfolípidos. La presencia de múltiples trombos en lechos vasculares pequeños que lleva a falla multiorgánica, simultáneamente o en menos de 1 semana, define al síndrome antifosfolípido catastrófico el cual conlleva alta mortalidad; sin embargo, la sospecha diagnóstica y la institución temprana del tratamiento, definitivamente inciden en el pronóstico de éstos pacientes(AU)

Antiphospholipid syndrome is defined by the combination of thrombotic and/or obstetric clinical manifestations and a persistently high and significant title of antiphospholipid antibodies. The presence of multiple thrombi in small vascular beds leading to multi-organ failure that occurs simultaneously or in less than 1 week, and defines the catastrophic antiphospholipid syndrome which carries high mortality, The suspected diagnosis and early treatment affects the prognosis of these patients(AU)

Significance of Lupus Anticoagulant in Children with Prolonged Prothrombin Time/activated Partial Thromboplastin Time / 임상소아혈액종양

BACKGROUND: The prolongation of prothrombin time (PT)/activated partial thromboplastin time (aPTT) in vitro occurs from various causes and lupus anticoagulant (LA) is one of them. This study was performed to investigate the association between prolonged PT/aPTT and LA in children. METHODS: This study included 66 subjects, who showed prolonged PT/aPTT on routine examination and screening test prior to an invasive procedure. LA was investigated in subjects with only PT prolongation, only aPTT prolongation, and PT/aPTT prolongation. The aPTT prolongation subjects were subdivided into more prolonged (≥60 sec) and less prolonged (39.6≤aPTT<60 sec). In addition, the sensitivity and specificity of LA in PT or aPTT prolongation was evaluated by ROC (receiver operating characteristics) curve. RESULTS: The frequency of LA positivity was 60.6% in PT or aPTT prolongation subjects. The frequency and titer of LA were higher in the order of prolonged PT group, prolonged aPTT group, and prolonged PT/aPTT (P<0.01). The frequency and titer of LA were higher in more prolonged aPTT group than less prolonged group (P<0.01). The accuracy of sensitivity and specificity of LA in cases with PT prolongation was low (area under the ROC curve was 0.68), however, was high (0.89) in cases with aPTT prolongation. The sensitivity and specificity of LA in predicting aPTT prolongation time of more than 42.9 sec were 0.83 and 1.00, respectively. CONCLUSION: PT was less affected than aPTT by LA and aPTT prolongation could more accurately predict LA existence. A large portion of PT or aPTT prolongation found in children without obvious past or family history of bleeding, especially accompanying infectious disease, might be associated with LA.

Significance of Lupus Anticoagulant in Children with Prolonged Prothrombin Time/activated Partial Thromboplastin Time / 임상소아혈액종양

BACKGROUND: The prolongation of prothrombin time (PT)/activated partial thromboplastin time (aPTT) in vitro occurs from various causes and lupus anticoagulant (LA) is one of them. This study was performed to investigate the association between prolonged PT/aPTT and LA in children.METHODS: This study included 66 subjects, who showed prolonged PT/aPTT on routine examination and screening test prior to an invasive procedure. LA was investigated in subjects with only PT prolongation, only aPTT prolongation, and PT/aPTT prolongation. The aPTT prolongation subjects were subdivided into more prolonged (≥60 sec) and less prolonged (39.6≤aPTT<60 sec). In addition, the sensitivity and specificity of LA in PT or aPTT prolongation was evaluated by ROC (receiver operating characteristics) curve.RESULTS: The frequency of LA positivity was 60.6% in PT or aPTT prolongation subjects. The frequency and titer of LA were higher in the order of prolonged PT group, prolonged aPTT group, and prolonged PT/aPTT (P<0.01). The frequency and titer of LA were higher in more prolonged aPTT group than less prolonged group (P<0.01). The accuracy of sensitivity and specificity of LA in cases with PT prolongation was low (area under the ROC curve was 0.68), however, was high (0.89) in cases with aPTT prolongation. The sensitivity and specificity of LA in predicting aPTT prolongation time of more than 42.9 sec were 0.83 and 1.00, respectively.CONCLUSION: PT was less affected than aPTT by LA and aPTT prolongation could more accurately predict LA existence. A large portion of PT or aPTT prolongation found in children without obvious past or family history of bleeding, especially accompanying infectious disease, might be associated with LA.

Inhibidor lúpico en situaciones clínicas diferentes al síndrome antifosfolipídico / Lupus inhibitor in clinical situations other than antiphospholipid syndrome

El inhibidor lúpico (IL) es uno de los criterios de laboratorio para Síndrome Antifosfolipídico (SAF); sin embargo, puede detectarse en individuos asintomáticos o estar asociado a otras situaciones clínicas. Presentamos un análisis retrospectivo de 1000 exámenes consecutivos para IL (TTPA, DRVVT) de los cuales 249 casos no presentaban criterios clínicos de SAF. Aplicando los criterios SSC-ISTH, hallamos IL+ en 27,30% (205/751) y 43,37% (108/249) de los casos con y sin criterios clínicos de SAF respectivamente; analizándose en estos últimos casos las características clínicas y de laboratorio. Contexto clínico de casos IL+ sin SAF: 18,52% asintomáticos, 34,26% síntomas de sangrado y 47,22% otras manifestaciones. Otras alteraciones de laboratorio en casos IL+ sin SAF, con síntomas de sangrado: detectamos alteraciones plaquetarias, descenso de VWF:RCo y/o VWF:Ag, disminución de FVIII, FV, FVII, FXI o fibrinógeno e hiperfibrinolisis en el 54,05% de los casos. El análisis mostró detección de IL+ en un número importante de estudios (108/1000) sin criterios SAF. Los casos con IL+ y sangrado representan un desafío particular, al requerir evaluar otros posibles defectos subyacentes, que pudiesen justificar el comportamiento clínico. La detección e identificación de defectos combinados requiriere de un análisis minucioso, a fin de alcanzar un diagnóstico correcto, esencial para tomar decisiones terapéuticas adecuadas. (AU)

Despite lupus anticoagulant (LA) is one of the laboratory criteria for antiphospholipid syndrome (APS), it can be present in asymptomatic subjects or it can be associated with other clinical settings. We present a retrospective analysis of 1000 consecutive LA assays (APTT, DRVVT), 249 of them were performed in patients without clinical criteria for APS. According to ISTH criteria, positive LA was found in 27.30% (205/751) and 43.37% (108/249) of cases with or without APS criteria respectively; in the last group, the analysis of clinical background and laboratory characteristics was done. Clinical background of LA+ cases without APS: 18.52% asymptomatic, 34.26% bleeding symptoms and 47.22% other clinical settings. Other abnormal laboratory tests in LA+ cases without APS and bleeding symptoms: platelet dysfunction; low VWF:RCo and/or VWF:Ag; decrease of FVIII, FV, FVII, FXI or fibrinogen and hyperfibrinolysis were found in the 54.05% of the cases. The analysis showed positive LA in an important number of cases (108/1000) without criteria of APS. Those LA+ cases with bleeding symptoms represent a particular challenge because other possible underlying defects have to be analysed in order to explain the clinical behaviour. The detection and identifications of combined defects required a careful analysis in order to achieve accurate diagnosis, essential for therapeutic decisions. (AU)