Coagulopatía y Covid-19. Recomendaciones para una realidad cambiante / Coagulopathy and COVID-19. Recommendations for a changing reality

La pandemia COVID-19 provocada por el betacoronavirus SARS-CoV-2 exige rápidas respuestas desde el campo de la medicina. El riesgo de tromboembolismo venoso y arterial está aumentado durante la infección, especialmente en pacientes críticos. En ese contexto se destaca una coagulopatía caracterizada por niveles elevados de dímero D, con tendencia a la falla multiorgánica, y aumento de la mortalidad. Esas anormalidades de la hemostasia responden a varios mecanismos que deben tenerse en cuenta para la toma de decisiones terapéuticas. Analizamos la evidencia científica disponible en la que se fundamenta el enfoque terapéutico de la coagulopatía descripta y sus complicaciones, con el objetivo de diseñar recomendaciones terapéuticas realistas tendientes a disminuir la morbilidad y la mortalidad en pacientes con COVID-19

The coronavirus disease 2019 (COVID-19) pandemic requires rapid medical responses. The risk of venous and arterial thromboembolism increases in critically ill patients with SARS-CoV-2 infection. There is a hypercoagulable state that includes elevated levels of D-dimer, with an increased risk of organ failure and increased mortality. The abnormalities described in hemostasis should be considered for therapeutic decision making. We analyzed the available scientific evidence for the therapeutic approach of coagulopathy in the course of the disease with the objective of designing realistic therapeutic recommendations aimed at reducing morbidity and mortality in patients with COVID-19

[Coagulopathy and COVID-19. Recommendations for a changing reality]. / Coagulopatía y COVID-19. Recomendaciones para una realidad cambiante.

The coronavirus disease 2019 (COVID-19) pandemic requires rapid medical responses. The risk of venous and arterial thromboembolism increases in critically ill patients with SARS-CoV-2 infection. There is a hypercoagulable state that includes elevated levels of D-dimer, with an increased risk of organ failure and increased mortality. The abnormalities described in hemostasis should be considered for therapeutic decision making. We analyzed the available scientific evidence for the therapeutic approach of coagulopathy in the course of the disease with the objective of designing realistic therapeutic recommendations aimed at reducing morbidity and mortality in patients with COVID-19.

La pandemia COVID-19 provocada por el betacoronavirus SARS-CoV-2 exige rápidas respuestas desde el campo de la medicina. El riesgo de tromboembolismo venoso y arterial está aumentado durante la infección, especialmente en pacientes críticos. En ese contexto se destaca una coagulopatía caracterizada por niveles elevados de dímero D, con tendencia a la falla multiorgánica, y aumento de la mortalidad. Esas anormalidades de la hemostasia responden a varios mecanismos que deben tenerse en cuenta para la toma de decisiones terapéuticas. Analizamos la evidencia científica disponible en la que se fundamenta el enfoque terapéutico de la coagulopatía descripta y sus complicaciones, con el objetivo de diseñar recomendaciones terapéuticas realistas tendientes a disminuir la morbilidad y la mortalidad en pacientes con COVID-19.

Coagulopatía y covid-19. recomendaciones para una realidad cambiante / Coagulopathy and COVID-19. Recommendations for a changing reality

Resumen La pandemia COVID-19 provocada por el betacoronavirus SARS-CoV-2 exige rápidas respuestas desde el campo de la medicina. El riesgo de tromboembolismo venoso y arterial está aumentado durante la infección, especialmente en pacientes críticos. En ese contexto se destaca una coagulopatía caracterizada por niveles elevados de dímero D, con tendencia a la falla multiorgánica, y aumento de la mortalidad. Esas anormalidades de la hemostasia responden a varios mecanismos que deben tenerse en cuenta para la toma de decisiones terapéuticas. Analizamos la evidencia científica disponible en la que se fundamenta el enfoque terapéutico de la coagulopatía descripta y sus complicaciones, con el objetivo de diseñar recomendaciones terapéuticas realistas tendientes a disminuir la morbilidad y la mortalidad en pacientes con COVID-19.

Abstract The coronavirus disease 2019 (COVID-19) pandemic requires rapid medical responses. The risk of venous and arterial thromboembolism increases in critically ill patients with SARS-CoV-2 infection. There is a hypercoagulable state that includes elevated levels of D-dimer, with an increased risk of organ failure and increased mortality. The abnormalities described in hemostasis should be considered for therapeutic decision making. We analyzed the available scientific evidence for the therapeutic approach of coagulopathy in the course of the disease with the objective of designing realistic therapeutic recommendations aimed at reducing morbidity and mortality in patients with COVID-19.

Radioimmunotherapy for mantle cell lymphoma: 5-year follow-up of 90 patients from the international RIT registry.

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) and for relapse in 45 (50%) patients. Most patients received 90Y-IT as consolidation after chemoimmunotherapy in first line (98%) and in relapse (53%). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%. and 1 pt. (2%) PD, and for 4 pts. (9%), no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95% CI, 1.03-2.32) years, and median OS was 4.05 (95% CI, 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib.

Radioimmunotherapy (RIT) for Follicular Lymphoma achieves long term lymphoma control in first line and at relapse: 8-year follow-up data of 281 patients from the international RIT-registry.

To assess efficacy of radioimmunotherapy (RIT) in follicular lymphoma, data from 281 patients collected in the RIT Network, with a median follow-up of 8·2 years after RIT were analysed. RIT was given at first line in 18·5% and at relapse in 81·5%. Following first line therapy, 76·9% achieved complete remission (CR), 9·6% partial remission (PR), 1·9% stable disease (SD) and 1·9% had progressive disease (PD); response was not documented in 9·7%. At relapse, the rate of CR was 48·5% and that of PR was 16·6%, SD 2·6% and PD 10·5%; response was not documented in 21·8%. After median follow-up of 8·2 years, median progression-free survival (PFS) for all was 2·54 years, median overall survival (OS) was not reached. Median PFS and OS (both not reached) were significantly better in first line, compared to RIT at relapse (PFS, 2·11 years; OS, 10·8 years; P = 0·0037 and P = 0·0021, respectively). Overall 8-year PFS was 33·9%, 53·6% for first line and 29·6% for relapsed individuals. Overall 8-year OS was 58·8%, 78·1% for first line and 54·5% for relapsed patients. Thirty-five patients (12·5%) developed secondary malignancy and 16 patients (5·7%) experienced transformation into aggressive lymphoma. RIT is a safe and effective treatment option for follicular lymphoma, both at front line and relapse with an 8-year PFS of 53·6% and 29·6%, respectively.

Radioimmunotherapy confers long-term survival to lymphoma patients with acceptable toxicity: registry analysis by the International Radioimmunotherapy Network.

UNLABELLED: The Radioimmunotherapy Network (RIT-N) is a Web-based, international registry collecting long-term observational data about radioimmunotherapy-treated patients with malignant lymphoma outside randomized clinical studies. The RIT-N collects unbiased data on treatment indications, disease stages, patients' conditions, lymphoma subtypes, and hematologic side effects of radioimmunotherapy treatment. METHODS: RIT-N is located at the University of Göttingen, Germany, and collected data from 14 countries. Data were entered by investigators into a Web-based central database managed by an independent clinical research organization. RESULTS: Patients (1,075) were enrolled from December 2006 until November 2009, and 467 patients with an observation time of at least 12 mo were included in the following analysis. Diagnoses were as follows: 58% follicular lymphoma and 42% other B-cell lymphomas. The mean overall survival was 28 mo for follicular lymphoma and 26 mo for other lymphoma subtypes. Hematotoxicity was mild for hemoglobin (World Health Organization grade II), with a median nadir of 10 g/dL, but severe (World Health Organization grade III) for platelets and leukocytes, with a median nadir of 7,000/µL and 2.2/µL, respectively. CONCLUSION: Clinical usage of radioimmunotherapy differs from the labeled indications and can be assessed by this registry, enabling analyses of outcome and toxicity data beyond clinical trials. This analysis proves that radioimmunotherapy in follicular lymphoma and other lymphoma subtypes is a safe and efficient treatment option.

Imatinib-induced fatal acute liver failure.

Imatinib mesylate is a drug that has been approved for treatment of chronic myeloid leukemia (CML) in blast crisis, accelerated or chronic phase, and also for advanced gastrointestinal stromal tumors. Severe hepatic toxicity and three deaths from hepatic failure have been reported. We report the case of a 51-year-old woman who was admitted to our institution with severe acute hepatitis. She was diagnosed with CML and began treatment with imatinib mesylate at a dose of 400 mg/d. Five months after beginning treatment, she developed severe hepatitis associated with coagulopathy, and was admitted to our institution. She had been consuming acetaminophen 500-1000 mg/d after the onset of symptoms. She had a progressive increase in bilirubin level and a marked decrease of clotting factor V. Five days after admission, grade II encephalopathy developed and she was referred for liver transplantation. Her clinical condition progressively deteriorated, and 48 h after being referred for transplantation she suffered a cardiac arrest and died. This report adds concern about the possibility of imatinib-mesylate-induced hepatotoxicity and liver failure, particularly in the case of concomitant use with acetaminophen. Liver function tests should be carefully monitored during treatment and, with the appearance of any elevation of liver function tests, treatment should be discontinued.

99mTechnetium-SESTAMIBI uptake in malignant lymphomas. Correlation with chemotherapy response.

BACKGROUND: The rationale of the present study is based on the property of technetium-SESTAMIBI to enter malignant and other highly metabolic cells, and then to be pumped out of them by the multidrug-resistant (MDR) system, strongly depending on the expression of the MDR-1 gene encoded P-glycoprotein (Pgp-170). METHODS AND RESULTS: Forty-one patients with malignant lymphoma were studied before chemotherapy. Images were taken 30 min (early) and 180 min (late) after intravenous injection of (99m)Tc-MIBI, and then visually interpreted. They were correlated with clinical response defined as chemosensitive (ChS) when a >6 month remission was attained, and chemoresistant (ChR) to any other response. Of 41 patients, 27 had an early positive uptake, 18 (67%) were ChS, and 9 (33%) ChR. Of these 27 patients, 19 also had late positive scans; 15 (79%) were ChS, and only 4 were ChR (p = 0.037). Conversely, 10 of 14 remaining patients with negative early scans were ChR. Eight patients had an early positive study; however, the late retention of (99m)Tc-MIBI was negative and the relationship to chemotherapy response was not conclusive. A breakdown of data was made according to histology. Patients with low grade lymphoma had the strongest correlation between (99m)Tc-MIBI uptake and chemosensitivity. Patients with high grade lymphoma had only a trend, and patients with Hodgkin's disease had an indefinable correlation. CONCLUSIONS: This study takes advantage of the relationship between the ability to uptake and retain (99m)Tc-MIBI, a Pgp-170 substrate, by lymphomatous tumors. This attribute, combined with other clinical data, could help to select tailored treatments for patients that are likely to be chemoresistant before treatment.

Oligonucleotide IMT504 induces an immunogenic phenotype and apoptosis in chronic lymphocytic leukemia cells.

Oligonucleotides (ODNs) of the PyNTTTTGT class directly stimulate B lymphocytes and plasmacytoid dendritic cells of the immune system of primates. Here we investigated the ability of the PyNTTTTGT ODN prototype IMT504 to regulate the expression of surface molecules and apoptosis in human B-chronic lymphocytic leukemia (CLL) cells. The surface molecules CD25, CD40, CD80 and CD86 were up-regulated upon incubation of the B-CLL cells with IMT504. Co-stimulation with IL-2 resulted in further up-regulation. IMT504-activated B-CLL cells were also good stimulators of T cells in allogeneic mixed lymphocyte reactions and co-stimulation with IL-2 improved this stimulation capacity. Apoptosis of the B-CLL cells in vitro was also stimulated by incubation with IMT504. In this case, co-stimulation with IL-2 was not significant. Furthermore, B-CLL cells of all the patients studied developed an immunogenic phenotype and entered stimulated apoptosis upon in vitro incubation with IMT504 independently of the mutational status of their IgV(H) genes, becoming a good marker for tumor progression.

Oligonucleotide imt504 induces an immunogenic phenotype and apoptosis in chronic lymphocytic leukemia cells

Los oligonucleótidos (ODNs) de tipo PyNTTTTGT estimulan directamente las células B y las células dendríticas plasmacitoides del sistema inmune de primates. En este trabajo, investigamos la habilidad del IMT504, prototipo de los ODN tipo PyNTTTTGT, para regular la expresión demoléculas de superficie y la apoptosis en células B de leucemia linfocítica crónica (LLC). La expresión de lasmoléculas de superficie CD25, CD40, CD80 y CD86 fue aumentada al incubar las células B-LLC con IMT504. La co-estimulación con IL-2 provocó un aumento mayor. Las células B-LLC activadas fueron buenas estimuladorasde las células T en cultivo mixto de linfocitos alogeneicos y la co-estimulación con IL-2 mejoró esta capacidad. La apoptosis de las células B-LLC también fue estimulada por incubación con IMT504. En este caso, la coestimulación con IL-2 no fue significativa. Más aún, las células B-LLC de todos los pacientes estudiados,desarrollaron un fenotipo inmunogénico y entraron en apoptosis luego de la incubación in vitro con IMT504,independientemente del estado mutacional de sus genes IgVH , un indicador del pronóstico de la patología.

Chronic lymphocytic leukemia developing in a patient with chronic myeloid leukemia: evidence of distinct lineage-associated genomic events.

We describe the cytogenetic, fluorescence in situ hybridization (FISH), and molecular findings in a patient who developed a typical chronic lymphocytic leukemia (CLL) 20 months after the diagnosis of a Philadelphia (Ph)-positive chronic myeloid leukemia. Unstimulated bone marrow culture showed a 46,XX,t(9;22)(q34;q11) karyotype, and interphase FISH detected the presence of a BCR/ABL fusion signal in 13% of cells. On stimulated bone marrow culture, a normal karyotype and a 13q14 deletion by interphase FISH with D13S319 probe in 14% of the cells were found. Molecular studies detected the chimeric BCR/ABL messengers by nested reverse-transcriptase polymerase chain reaction. The B-cellular clone was documented by the presence of a clonal heavy chain immunoglobulin rearrangement. The coexistence of these two hematologic malignancies leads to questions about their cell(s) of origin. We provide evidence that CLL arose in a Ph-negative clone. The implications of these findings are discussed.

Necesidad de registro para evitar transfusiones azarosas entre consanguíneos / Measures to prevent consanguineous transfusion

Fundamento: la enfermedad injerto contra huésped relacionada con transfusión (EIcH-T) es una complicación de la transfusión entre consanguíneos y habitualmente no se registra este último evento en la documentación de los Servicios de Hemoterapia. Objetivos: determinar la importancia de registro de la consanguinidad a efectos de evitar EIcH-T por transfusiones azarosas entre consanguíneos. Material y método: de enero de 2001 a mayo de 2003 fue registrada la presencia de consanguinidad entre dadores y pacientes en el libro de donantes y en las bolsas madre y satélite de plaquetas; las donaciones fueron, dirigidas y no dirigidas. Se registraron 10.827 donaciones de sangre, de las que se obtuvieron 18.406 unidades de hemocomponentes celulares aptos para transfusión. De ellas, 1.868 donantes (17,3 por ciento) fueron consanguíneos con el paciente, y se obtuvieron 3.324 unidades de hemocomponentes (18 por ciento) aptas para transfusión. A efectos de investigar las chances de transfusión azarosa de hemocomponentes a consanguíneos, fueron excluídas para el análisis de probabilidades las siguientes unidades: 1) unidades ABO/Rn incompatibles, 157 (4,7 por ciento). 2) unidades ya transfundidas o dadas de baja al momento de la solicitud de transfusión, 304 (9,1 por ciento). 3) unidades no donadas al momento de la solicitud de transfusión (donantes de reposición), 504 (15,2 por ciento). 4) unidades irradiadas (por consanguinidad, inmunodeficiencias, etc.), 624 (18,8 por ciento). 5) unidades no transfundidas por no existir solicitud de transfusión para el paciente consanguíneo, 846 (25,5 por ciento). Resultados: Las unidades provenientes de consanguíneos y en condiciones de ser transfundidas a un paciente consanguíneo, fueron 889 de 3.324 (26,7 por ciento). Según el libro de contabilidad, al momento de las solicitudes de transfusión para consanguíneos, la sumatoria ponderada de todos los saldos de hemocomponentes provenientes de consanguíneos, fue de 1.067 unidades. Asimismo, al momento de las solicitudes de transfusión para consanguíneos, la sumatoria ponderada de todos los saldos de hemocomponentes no provenientes de consanguíneos, fue de 28.720 unidades. En este estudio, la probabilidad porcentual de que un paciente reciba al menos una unidad de hemocomponente proveniente de un consanguíneo de forma aleatoria es de [1.067/28.720 + 1.067] x 100= 3,6 por ciento...

[Spontaneous spleen rupture associated to active cytomegalovirus infection]. / Ruptura espontánea de bazo asociada a infección activa por citomegalovirus.

We present a 24 year old immunocompetent male who developed a spontaneous rupture of the spleen (SRE) during an acute cytomegalovirus (CMV) infection. The only previous clinical feature was the presence of flu-like symptoms two weeks before the SRE. The diagnosis was confirmed by the presence of IgM antibodies to CMV in the serum and a positive CMV-PCR in the splenic biopsy after splenectomy. The patient recovered completely after surgery. Spontaneous splenic rupture is an uncommon event associated with primary cytomegalovirus infection, and this is the first case reported in our country.

Ruptura espontanea de bazo asociada a infeccion activa por citomegalovirus / Spontaneous spleen rupture associated to active cytomegalovirus infection

We present a 24 year old immunocompetent male who developed a spontaneous rupture of the spleen (SRE) during an acute cytomegalovirus (CMV) infection. The only previous clinical feature was the presence of flu-like symptoms two weeks before the SRE. The diagnosis was confirmed by the presence of IgM antibodies to CMV in the serum and a positive CMV-PCR in the splenic biopsy after splenectomy. The patient recovered completely after surgery. Spontaneous splenic rupture is an uncommon event associated with primary cytomegalovirus infection, and this is the first case reported in our country