Acute arterial ischemia in COVID-19 / Isquemia arterial aguda em pacientes com COVID-19

Abstract Since the coronavirus pandemic set in in Spain in March 2020, a noteworthy increase in the incidence of acute limb ischemia (ALI) has been observed. It has been recently discovered that SARS-CoV 2 may lead to ALI secondary to arterial thrombosis. Elevation of D-dimer (DD) in patients with coronavirus infection (COVID-19) indicates that a hypercoagulable state causes acute arterial thrombosis. A remarkably high DD elevation has been reported to be a poor prognosis factor in COVID-19. The ways in which SARS-CoV 2 results in arterial thrombosis may be multiple. On the other hand, surgical revascularization for ALI is associated with poor outcomes in COVID-19 patients, probably in relation to hypercoagulability. Here, we describe two ALI cases in patients who required urgent surgical treatment for limb salvage and were positive for the novel coronavirus infection (COVID 19).

Resumo Desde que a pandemia pelo novo coronavírus se estabeleceu na Espanha, em março de 2020, um aumento notável da incidência de isquemia aguda de membros foi observado. Recentemente, descobriu-se que o coronavírus 2 causador da síndrome respiratória aguda grave (SARS-CoV-2) pode ocasionar isquemia aguda de membros secundária à trombose arterial. A elevação do D-dímero em pacientes acometidos pela doença do novo coronavírus (COVID-19) indica o estado de hipercoagulabilidade como causa da trombose arterial aguda. Vale destacar que a alta elevação do D-dímero foi relatada como um fator de prognóstico reservado na COVID-19. Há diversas maneiras pelas quais o SARS-CoV-2 pode resultar em trombose arterial. Em pacientes com COVID-19, a revascularização cirúrgica para isquemia aguda de membros está associada a desfechos desfavoráveis, provavelmente relacionados a hipercoagulabilidade. Descrevemos dois casos de isquemia aguda de membros de pacientes que necessitaram de tratamento cirúrgico de urgência para salvamento de membro e que haviam testado positivo para COVID-19.

Caracterización de neonatos de madres con hipercoagulabilidad en régimen tromboprofiláctico / Characterization of neonates of mothers with hypercoagulability in thromboprophylactic regimen

Introducción: Hace una década, en el Instituto de Hematología e Inmunología se comenzó la tratamiento de mujeres con pérdidas recurrentes de embarazos por trastornos de hipercoagulabilidad. Objetivo: Caracterizar clínicamente a estos neonatos e identificar los efectos adversos de la terapia tromboprofiláctica en los recién nacidos. Métodos: Se realizó estudio descriptivo, de corte transversal entre enero de 2014 y agosto de 2017, que incluyó 62 recién nacidos, hijos de madres con diagnóstico de trombofilia que utilizaron durante la gestación, régimen de tromboprofilaxis con heparinas de bajo peso molecular y aspirina. Todas las gestantes fueron evaluadas con sistematicidad en las consultas de Hemostasia y Obstetricia, del Instituto de Hematología e Inmunología y Hospital Enrique Cabrera, respectivamente. Resultados: La mayoría de los neonatos nacieron a término, con apgar normal y pesos superiores a 2 500 g. El 82,3 por ciento de las gestantes comenzaron la tromboprofilaxis con menos de 5 semanas de gestación. Hubo diferencias significativas cuando se compararon los pesos de los neonatos de las madres que comenzaron el tratamiento temprano con aquellas que lo iniciaron tardíamente. El tipo de trombofilia y la edad materna no influyeron en los pesos de los neonatos, pero aquellas gestantes con sintomatología más grave tuvieron hijos de menor peso que, aunque no fue significativo, requiere una observación. Ningún recién nacido presentó efectos secundarios a la terapia tromboprofiláctica. Conclusiones: Los neonatos nacidos de madres con trombofilia que iniciaron tromboprofilaxis de forma temprana no fueron diferentes a los recién nacidos de madres sin hipercoagulabilidad(AU)

Introduction: A decade ago, at the Institute of Hematology and Immunology, treatment of women with recurrent pregnancy losses due to hypercoagulability disorders began. Objective: Clinically characterize these infants and identify the adverse effects of thromboprophylactic therapy in newborns. Methods: A descriptive and transversal study was carried out between January 2014 and August 2017, which included 62 children of mothers with a diagnosis of thrombophilia who used during pregnancy, a thromboprophylaxis regimen with low molecular weight heparins and aspirin. All pregnant women were systematically evaluated in the Hemostasis and Obstetrics consultations of the Institute of Hematology and Immunology and Hospital Enrique Cabrera. Results: The majority of the neonates were born at term, with normal apgar and weights above 2,500 g. 82.3 percent of pregnant women started thromboprophylaxis with less than 5 weeks of gestational age. There were significant differences when the weights of the infants of the mothers who started the treatment early were compared with those who started it late. The type of thrombophilia and maternal age did not influence the weights of the neonates, but those cases with more severe symptoms had children of lower weight, which although it was not significant, requires observation. No newborn presented side effects to thromboprophylactic therapy. Conclusions: Infants born to mothers with thrombophilia who started thromboprophylaxis early were not different from those born to mothers without hypercoagulability(AU)

Mutación g20210a del gen de la protrombina: presentación clínica en dos gestantes / G20210a mutation of the prothrombin gene: clinical presentation in two pregnant women

La trombofilia hereditaria es una enfermedad genética que resulta de dos o más mutaciones en genes involucrados en el sistema hemostático, con variabilidad en la penetrancia del fenotipo trombótico. Entre los genes mutados asociados al incremento del riesgo de trombosis venosa se encuentra la mutación G20210A del gen de la protrombina. Se presentan los casos de dos pacientes jóvenes embarazadas que acudieron a la consulta de Hemostasia del Instituto de Hematología e Inmunología. Una, con historia personal de enfermedad tromboembólica (ETE) asociada al uso de anticonceptivos orales; y la otra, con antecedentes familiares de ETE e historia personal de abortos recurrentes. A ambas pacientes se les realizó estudio de trombofilia en el que se detectó la mutación G20210A del gen de la protrombina en estado heterocigoto. Recibieron seguimiento médico multidisciplinario y tratamiento profiláctico con aspirina a bajas dosis hasta la semana 34 de la gestación; y heparina de bajo peso molecular durante la gestación y seis semanas después del parto. Se lograron dos nacimientos sin complicaciones obstétricas ni fetales. La expresión de gen de la protrombina G20210A es variable, incluso dentro de una misma familia, y puede estar influenciada por factores de riesgo adquiridos, como el uso de anticonceptivos orales, el embarazo y el puerperio(AU)

Hereditary thrombophilia is a genetic disease that results from two or more mutations in genes involved in the hemostatic system, with variable penetrance of the thrombotic phenotype. Among the mutated genes associated with increased risk of venous thrombosis is mutation G20210A prothrombin gene. We present two pregnant young patients who attended the Haemostasis outpatient service at the Institute of Hematology and Immunology. One of them, with personal history of thromboembolic disease (TED) associated with use of oral contraceptives; and the other one, with a family history of TED and personal history of recurrent abortions. In both patients´ thrombophilia studies the G20210A mutation in the prothrombin gene in heterozygous state was detected. The patients received multidisciplinary medical monitoring and prophylactic treatment with low-dose aspirin until week 34 of gestation, and low molecular weight heparin during pregnancy and six weeks after delivery. Two births without obstetric or fetal complications were achieved. The gene expression of prothrombin G20210A is variable, even within the same family and may be influenced by acquired risk factors such as the use of oral contraceptives, pregnancy and the postpartum period(AU)

Systematic review: hereditary thrombophilia associated to pediatric strokes and cerebral palsy / Revisão sistemática: trombofilias hereditárias associadas aos acidentes vasculares cerebrais pediátricos e a paralisia cerebral

OBJECTIVES: This review aimed to organize and consolidate the latest knowledge about mutations and genetic polymorphisms related to hereditary thrombophilia and their potential association with pediatric stroke and cerebral palsy (CP). SOURCES: Scientific articles published from 1993 to 2013, written in Portuguese, English, French, and Spanish, were selected and reviewed. The publications were searched in electronic databases, and also in the collections of local libraries. The terms "hereditary thrombophilia", "polymorphisms", "mutation", "pediatric strokes", and "cerebral palsy" were used for the research. SUMMARY OF THE FINDINGS: The search in databases and in the bibliographic references retrieved 75 articles for inclusion in this review. Studies that investigated hereditary thrombophilias and their associations to CP and arterial and venous pediatric stroke presented contradictory results. The meta-analysis and case-control studies that showed positive results for this association described only slightly increased relative risks and sometimes had questionable conclusions. The association of two or more hereditary thrombophilias, or the association between thrombophilia and other specific clinical risk factors, suggest a higher risk of CP and pediatric stroke than isolated hereditary thrombophilia. CONCLUSIONS: Larger, multicenter studies should be developed in order to elucidate the role of mutations leading to hereditary thrombophilia and the development of CP and pediatric stroke. The complex and multifactorial etiology of CP and stroke makes this an arduous and difficult task; however, the benefits generated by these studies are immeasurable. .

OBJETIVO: Sistematizar e integrar os últimos conhecimentos sobre mutações e polimorfismos genéticos relacionados às trombofilias hereditárias e suas potenciais associações com acidentes vasculares cerebrais pediátricos (AVC) e paralisia cerebral (PC). MATERIAL: Artigos científicos publicados de 1993 a 2013, escritos em português, inglês, francês e espanhol foram selecionados e revisados. As publicações foram pesquisadas nas bases de dados eletrônicas, como também nos acervos das bibliotecas locais. Os termos mutação, polimorfismos, trombofilias hereditárias, acidentes vasculares cerebrais pediátricos e paralisia cerebral foram usados para a pesquisa. RESULTADOS: A pesquisa nas bases de dados e nas referências bibliográficas identificou 75 artigos para inclusão nesta revisão. Os estudos que investigaram as trombofilias hereditárias e suas associações à PC e aos AVC pediátricos arteriais e venosos apresentaram resultados contraditórios. As metanálises e os estudos caso-controle que demonstraram resultados positivos para essa associação descreveram riscos relativos discretamente aumentados e, algumas vezes, questionáveis. A associação de duas ou mais trombofilias hereditárias, ou a junção de trombofilias específicas com demais fatores de riscos clínicos, sugerem maior risco no aparecimento da PC e do AVC pediátrico do que as trombofilias hereditárias isoladas. CONCLUSÃO: Estudos multicêntricos de grande porte devem ser conduzidos para elucidar o papel real das mutações que levam às trombofilias hereditárias e ao aparecimento da PC e AVC pediátricos. A etiologia multifatorial e complexa da PC e dos AVC torna essa tarefa árdua e difícil, porém, os benefícios gerados por esses estudos são incalculáveis. .

Eventos tromboembólicos na gestação e puerpério: revisão sistemática e recomendação atual / Thromboembolic events in pregnancy and puerperium: systematic review and current recommendation

Os eventos tromboembólicos são a principal causa de morte materna em países desenvolvidos. A incidência desses eventos varia entre 0,76 a 1,72 a cada 1.000 gestações, sendo quatro a cinco vezes mais frequente que em mulheres não grávidas. Dois terços dos casos de trombose venosa profunda ocorrem durante a gestação e são igualmente distribuídos nos três trimestres, enquanto 43 a 60% dos episódios de embolia pulmonar ocorrem no período puerperal. Os principais fatores de risco são: história familiar ou pessoal,trombofilia, idade maior que 35 anos, obesidade, multiparidade e cesariana. Este artigo propôs-se a revisar o mecanismo fisiopatológico dos eventos tromboembólicos na gestação, sua terapia e profilaxia; comparando as diversas opções terapêuticas quanto aos benefícios e aos riscos maternos e fetais. Sempre que disponíveis são oferecidos os graus de recomendação de cada conduta adotada.(AU)

Thromboembolic events are the leading cause of maternal death in developed countries, with an incidence that varies from 0.76 to 1.72 per 1,000 pregnancies, four to five times more frequent than in non-pregnant women. Two-thirds of deep venous thrombosis cases occur during pregnancy, equally distributed within the three trimesters, while 43?60% of pulmonary embolism events occur during postpartum. Important risk factors include: personal or family history, thrombophilia, age over 35, obesity, multi-parity and prior cesarean. This article aimed to review the pathophysiological mechanism of thromboembolic events during pregnancy, its treatment and prophylaxis; analyzing various treatment options, their benefits and comparing their maternal and fetal risks. Each degree of recommendation is shown when available.(AU)

Deficiencia de proteínas C y S: marcadores de riesgo trombótico / Deficiency of proteins C and S: trombotic risk markers

Desde hace varios siglos se conoce que los defectos de la coagulación causan enfermedades hemorrágicas, pero el estudio de su contraparte, las enfermedades trombóticas, se ha desarrollado con mayor profundidad hace solo algunas décadas. Son estos trastornos del sistema de la coagulación los que constituyen una de las causas más comunes de muerte en el mundo de hoy donde cada año mueren alrededor de 2 millones de personas por trombosis, ya sea arterial o venosa. Además, se consideran una fuente importante de morbilidad en las personas que las padecen y sobreviven. Los estados de hipercoagulabilidad o trombofilias son condiciones clínicas que afectan a una serie de pacientes con tendencia anormal a presentar eventos trombóticos. La deficiencia de proteína C (PC) y proteína S (PS) constituyen causas de trombofilias congénitas o adquiridas que predisponen a la aparición de trastornos tromboembólicos, pérdidas recurrentes de embarazos, trombosis venosas recurrentes, entre otros. Su diagnóstico es de gran importancia porque permite realizar profilaxis para evitar el riesgo de recurrencia e informa sobre la posibilidad de un estado de portador en cualquier otro miembro de la familia

For several centuries it has been known that coagulation defects cause hemorrhagic disease, but the study of its counterpart, thrombotic diseases, has been developed in more depth just a few decades ago. These disorders of coagulation system are one of the most common causes of death in the world today, where about two million people die every year from thrombosis, either arterial or venous. They are also considered an important source of morbidity in people who suffer it and survive. Hypercoagulable state or thrombophilia are clinical conditions that affect a number of patients with abnormal tendency to thrombotic events. Deficiency of protein C (PC) and protein S (PS) are causes of congenital or acquired thrombophilias that predispose to thromboembolic disorders, recurrent pregnancy loss, recurrent venous thrombosis, among others. Its diagnosis is very important it provides tools for its prophylaxis in order to reduce the risk of recurrence and the possibility of identify a carrier state in any other family member

Coagulation inhibitors and activated protein C resistance in recurrent pregnancy losses in Indian women.

Background: Thrombophilias, both acquired and inherited, have been investigated in the etiopathogenesis of unexplained recurrent pregnancy loss. Aim: To study coagulation inhibitors and activated protein C resistance (APCR) in recurrent pregnancy losses (RPL) occurring in second and third trimesters. Materials and Methods: A total of 30 pregnant women (group A) with two or more recurrent unexplained fetal loses were evaluated for APCR, protein C deficiency, protein S deficiency, antithrombin deficiency, and antiphospholipid antibodies (APLA). Thirty age-matched controls were taken (group B) comprising of pregnant women with at least one live issue. Statistical Analysis: Comparisons between two group frequencies and group means were made using Chi square test and Student's t test, respectively. Results: Protein C and protein S levels were reduced in group A compared with group B and the difference was statistically significant (P=0.005 and P=0.032, respectively). The mean value of antithrombin was slightly reduced in group A compared with group B. APCR was observed in 16.6% cases and 3.3% controls. However, the difference was not statistically significant. APLA was observed in 20% cases and none of the controls. Of these, lupus anticoagulant was positive in 16.6% cases and anticardiolipin antibodies in 10% cases. Combined defects were seen in seven patients. Conclusion: There is a significant risk of RPL in pregnant women with thrombophilias. Therefore, screening for thrombophilias may be justified in pregnant women with unexplained recurrent fetal wastage, especially in second and third trimester.

Importancia del estudio con D-Dímeros en el control biológico del embarazo en pacientes con trombofilia / Importance of D Dimer testing in the biologic control of pregnancy in patients with thrombophilia

Los D-Dímeros por la técnica de ELISA aumentan progresivamente en eltranscurso del embarazo normal y en las pacientes con trombofilia. Son útilescomo control biológico en estas pacientes para detección precoz de complicacionesy poder ajustar dosis del tratamiento con heparina de bajo pesomolecular. El objetivo del trabajo es determinar si los D-Dímeros por otrastécnicas (D-Dímeros: BCS [Enol]) y D-Dímeros: STA Compact (Roche) sonde utilidad en la embarazada con trombofilia o con sospecha de ella. Resultados:de las 226 pacientes analizadas, 93 no presentaron complicacionesy, si bien existe un aumento leve de los valores de la mediana de D-Dímerohacia el final del embarazo, el aumento no alcanza los niveles esperados. Enlas 133 pacientes que presentaron complicaciones no se demostró aumentodestacable de D-Dímero vinculable a la presencia de ninguna de las complicaciones.Conclusión: no se demostró, con las técnicas utilizadas BCS (Enol)y STA Compact (Roche), la variación esperada del D-Dímero en los distintostrimestres del embarazo, ni con la presencia complicaciones, en pacientescon trombofilia, a diferencia de lo publicado sobre D-Dímero con la técnicade ELISA.

Relación de trombofilia con infertilidad y pronóstico reproductivo en técnicas de reproducción asistida de alta complejidad: revisión sistemática / Association of thrombophilia with infertility and reproductive prognostic in assisted reproductive technology: a systematic review

Cerca del 10 por ciento de las parejas no podrán conseguir un embarazo luego de estar expuesta a doce meses de coito sin protección, y deberán ser sometidas a algún tipo de técnica de reproducción asistida para conseguir un embarazo. En esta revisión sistemática buscamos determinar si hay evidencia que el tratamiento de trombofilia, endógena o exógena, en pacientes sometidas a técnicas de reproducción asistida mejora la tasa de embarazo. Encontramos un total de 29 publicaciones, de las que 6 fueron incluidos en el análisis. Los estudios observacionales muestran una asociación entre trombofilia e infertilidad, sin embargo, no existe evidencia para concluir si existe causalidad o no. No encontramos evidencia concluyente que el tratamiento profiláctico mejore la tasa de embarazo en mujeres infértiles sometidas a fecundación in vitro.

Around 10 percent of couple will not achieve pregnancy after 12 months of exposure, and will undergo assisted reproductive technology. In this systematic review we seek to determine whether the treatment of trombophilia, both exogenous and endogenous, increase or not the clinical pregnancy rate. We found 29 articles, 6 were included in the analysis. We found evidence that there is an association of thrombophilia and infertility, but not that the treatment improve the clinical pregnancy rate in women undergoing in vitro fertilization.