Consensus on the investigation of thrombophilia in women and clinical management / Consenso sobre a investigação de trombofilia em mulheres e manejo clínico

ABSTRACT Objective To standardize the investigation and clinical management of women with laboratory and/or clinical abnormalities suggestive of thrombophilia, in order to optimize antithrombotic approach and indication of laboratory tests. Methodology A discussion was carried out among 107 physicians (gynecologists/obstetricians, hematologists and vascular surgeons) present at a forum held at the Hospital Israelita Albert Einstein, in São Paulo (SP), Brazil. As a minimum criterion, 80% agreement was established in the voting to each recommendation of conduct in the final document. The cases in which there was agreement below 80% were discussed again, reaching a consensual agreement of conduct for the document writing. Conclusion The standardization of an institutional consensus of suggestions of clinical approach contributes to a better management of the group to be evaluated and minimizes risks of intercurrent events. This was the first national consensus on the investigation of thrombophilia in women.

RESUMO Objetivo Padronizar a investigação e o manejo clínico de mulheres com anormalidades clínicas e exames laboratoriais sugestivos de trombofilia, para melhorar a abordagem antitrombótica e otimizar a indicação de exames laboratoriais. Metodologia Foi conduzida discussão incluindo 107 médicos (ginecologistas/obstetras, hematologistas e cirurgiões vasculares) participantes de um fórum realizado no Hospital Israelita Albert Einstein, em São Paulo (SP). Como critério mínimo, estabeleceu-se concordância de 80% em votação para cada recomendação de conduta registrada em documento como diretrizes finais. Os casos em que a concordância esteve abaixo de 80% foram rediscutidos, para definir consenso na conduta. Conclusão A padronização e o estabelecimento de consenso institucional, com sugestões para abordagem clínica, contribui para melhorar o manejo do grupo a ser avaliado e minimizar os riscos de intercorrências. Este foi o primeiro consenso nacional sobre investigação de trombofilia em mulheres.

Alteraciones de la hemostasia en el síndrome drepanocítico / Hemostasis alterations in sickle cell syndrome

El síndrome drepanocítico (SD) comprende un grupo de anemias hemolíticas hereditarias de tipo multisistémico asociadas a la hemoglobina S. Los pacientes que padecen este síndrome tienen un mayor riesgo, en comparación con individuos sanos, de presentar accidentes cerebrovasculares, hipertensión pulmonar, necrosis avascular de articulaciones, síndrome torácico agudo y complicaciones durante el embarazo, asociados a un estado de hipercoagulabilidad inducido por alteraciones en los diferentes componentes de la hemostasia, que incluyen la activación del endotelio y de los sistemas plaquetario, de la coagulación y de la fibrinólisis. Esta revisión resume las alteraciones en la hemostasia reportadas en los pacientes con SD, en los cuales se ha demostrado: mayor interacción de células endoteliales con leucocitos, hematíes y plaquetas; aumento de la expresión de proteínas de adhesión, como el factor von Willebrand y sus multímeros de alto peso molecular; aumento de la adhesión y la agregación plaquetaria y de la expresión de proteínas en sus membranas. En el sistema de coagulación se ha detectado aumento en la expresión del factor tisular (FT) en micropartículas derivadas de diferentes células, aumento de marcadores de activación de este sistema, entre estos los fragmentos 1.2 de la protrombina y los complejos trombina-antitrombina y una disminución de las proteínas C y S que actúan como anti-coagulantes. Adicionalmente, se han encontrado aumentados los marcadores de activación del sistema fibrinolítico como los dímeros D y los complejos plasmina/antiplasmina. Todas estas manifestaciones favorecen la aparición de complicaciones trombóticas, implicadas en el deterioro de la calidad de vida de los pacientes. Se recomienda implementar en el diagnóstico y seguimiento de esta enfermedad, la determinación de variables del sistema hemostático, con el fin de identificar alteraciones en etapas tempranas y aplicar terapias que puedan prevenir complicaciones trombóticas.

Sickle cell syndrome (SCS) includes a group of congenital hemolytic anemias associated to the presence of hemoglobin S, which is characterized by acute pain episodes and progressive damage of different organs. Some patients with sickle cell syndrome have shown, when compared with healthy individuals, an increased risk of presenting stroke, pulmonary hypertension, avascular necrosis of joints, acute chest syndrome and pregnancy complications, associated to a hypercoagulable state induced by alterations in different components of hemostasis, such as changes that include activation of the endothelium, platelet activity, coagulation and fibrinolytic systems. This paper compiles hemostasis disorders, associated with thrombotic manifestations, reported until now in sickle cell syndrom. These patients have an increase in activation markers of the coagulation system, such as prothrombin fragment 1.2, thrombin-antithrombin complex, etc., depletion of natural anticoagulant proteins, abnormal activation of the fibrinolytic system and increased tissue factor expression. Similarly, abnormal expression of glycoproteins and increased adhesion and platelet aggregation have been reported. All these alterations produce a hypercoagulable state, which induces, among other things, the appearance of thrombotic complications. In view of the importance of controlling the different complications that can occur in patients with sickle cell syndrome, we recommend the implementation, in diagnosis and monitoring studies, of the evaluation of the different components of the hemostatic system, identifying alterations at an early stage and applying effective treatments to prevent thrombotic complications.

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

Clinical profile, common thrombophilia markers and risk factors in 85 young Indian patients with arterial thrombosis / Perfil clinico, marcadores comuns de trombofilia e fatores de risco em 85 pacientes indianos jovens com trombose arterial

CONTEXT AND OBJECTIVE: Arterial thrombosis may occur consequent to hereditary thrombophilia and increased lipoprotein(a) [Lp(a)] and fibrinogen. Our aim was to study the prevalence of common thrombophilia markers in 85 consecutive cases of arterial thrombosis. DESIGN AND SETTING: A retrospective study was conducted from 85 consecutive young patients treated as outpatients or admitted due to stroke or myocardial infarction at a tertiary care hospital. METHODS: Eighty-five Indian patients (age < 45 years) presenting ischemic stroke (n = 48) or myocardial infarction (n = 37) and 50 controls were studied for seven thrombophilia markers including antithrombin (AT), factor V, protein C, protein S, activated protein C resistance (APC-R), fibrinogen and Lp(a). Functional assays for protein C, protein S, factor V and APC-R were performed using clotting-based methods. Semi-quantitative estimation of fibrinogen was done using Clauss's method and Lp(a) using immunoturbidimetry. Statistical analysis was done using the Epi Info 6 software. RESULTS: Thirty-three samples (38.8%) tested positive for one or more thrombophilia markers. The three commonest abnormalities were elevated Lp(a) (20%), fibrinogen (17.6%) and low APC-R (14.2%). Low levels of protein C, protein S and AT were present in 4.7, 9.4 and 7% of the patients, respectively. Overall, the risk factor profile was: smoking (33%), positive family history (15.3%), hyperlipidemia (7%), hypertension, diabetes mellitus and obesity (2.3% each). CONCLUSIONS: An association was found between low levels of protein C, protein S and AT and arterial thrombosis, but only elevated fibrinogen levels, smoking, positive family history and hyperlipidemia showed statistical significance. .

CONTEXTO E OBJETIVO: Trombose arterial pode ocorrer em consequência de trombofilias hereditárias e de lipoproteína (a) [Lp (a)] e fibrinogênio aumentados. Nosso objetivo foi estudar a predominância de marcadores comuns da trombofilia em 85 casos consecutivos de trombose arterial. TIPO DE ESTUDO E LOCAL: Um estudo retrospectivo foi realizado sobre 85 pacientes jovens tratados consecutivamente no ambulatório ou admitidos por infarto do miocárdio ou acidente vascular cerebral (AVC) num hospital de cuidado terciário. MÉTODOS: Oitenta e cinco pacientes indianos (idade < 45 anos) que se apresentaram com AVC isquêmico (n = 48) ou infarto do miocárdio (n = 37) e 50 controles foram estudados para sete marcadores de trombofilia que incluíram antitrombina (AT), fator V, proteína C, proteína S, resistência ativada da proteína C (APC-R), fibrinogênio e Lp (a). Os ensaios funcionais da proteína C, proteína S, fator V e APC-R foram executados por métodos baseados em coagulação. A avaliação semiquantitativa do fibrinogênio foi feita pelo método de Clauss e a Lp(a) por imunoturbimetria. A análise estatística foi feita pelo software Epi Info 6. RESULTADOS: Trinta e três amostras (38.8%) foram positivas para um ou vários marcadores do trombofilia. As anomalias mais comuns foram Lp (a) (20%), fibrinogênio (17.6%) e APC-R (14.2%) elevados. Baixos níveis da proteína C, proteína S e AT foram detectados em 4.7%, 9.4% e 7% dos pacientes, respectivamente. Globalmente, os perfis dos fatores de risco foram: fumo (33%), antecedentes familiares positivos (15.3%), hiperlipidemia (7%), hipertensão, diabetes mellitus e obesidade (2.3% cada). CONCLUSÕES: Uma associação foi encontrada entre baixos níveis de proteína C, proteína S, AT e trombose arterial, ...

Efecto de los anticuerpos antifosfolipídicos en la formación y degradación de la malla de fibrina en pacientes con aborto recurrente / Effect of antiphospholipid antibodies on the formation and lysis of fibrin network in patients with recurrent miscarriage

En el presente trabajo se estudió el proceso de formación y disolución de la malla de fibrina y la generación de plasmina en un grupo de pacientes con aborto recurrente (AR) debido a la presencia de anticuerpos antifosfolipídicos (N= 10), mujeres con AR sin el síndrome antifosfolipídico (SAF) (N= 6) y se comparó con un grupo de mujeres sanas (N= 8). Del grupo de pacientes estudiadas con SAF, nueve fueron positivas para anticuerpos anticardiolipina (aCL), cinco para la anti-b2-glicoproteína I (anti-b2GPI), cuatro para ambos anticuerpos, una para anticuerpos antiprotrombina (aPT) y anticoagulante lúpico (AL). El proceso de formación de la fibrina y su disolución fue estudiado por turbidimetría y la generación de plasmina mediante sustrato cromogénico S2251. Las curvas de polimerización de la(s) paciente(s) con AR sin SAF y AL presentaron un incremento en la pendiente y turbidez final, comparado con las del grupo control de mujeres sanas. La velocidad de disolución del coágulo fue mayor en la paciente con AL (21 ± 0) 10-4 DDO/seg y en las AR sin SAF (19,6 ± 5,7) 10-4 DDO/seg, comparado con el grupo control (14,5 ± 2,8) 10-4 DDO/seg. La generación de plasmina estuvo incrementada solamente en las AR sin SAF (85 ± 24%) comparado con 52 ± 3% en el grupo control, p= 0,005. Los cambios observados en el proceso de polimerización y fibrinólisis de la(s) paciente(s) con AR sin SAF y AL pudieran estar relacionados con el incremento en los niveles de fibrinógeno, mientras que los de la generación de plasmina con la entidad mórbida.

The present work was intended to study the process of fibrin formation and lysis and plasmin generation in a group of patients with recurrent miscarriage (RM), due to the presence of antiphospholipid antibodies (N= 10); as well as in women with RM without the antiphospholipid syndrome (APS) (N= 6), compared with those of a group of healthy women (N= 8). In the group of patients with APS, nine were positive for antibodies against cardiolipin (aCL), five for anti-b2-glycoprotein I (anti-b2GPI), four for both antibodies, and one for antibodies against prothrombin (aPT) and lupus anticoagulant (LA). Fibrin formation and lysis was followed by turbidity and plasmin generation using chromogenic substrate S2251. The polymerization curves from RM patients without APS and the LA patient showed an increased slope and maximum turbidity compared to those of the control group. The speed of lysis was higher in the LA patient (21 ± 0) 10-4 DOD/seg and the RM patients without APS (19.6 ± 5.7) 10-4 DDO/seg, compared to that of the control group (14.5 ± 2.8) 10-4 DDO/seg. Plasmin generation increased only in RM patients without APS (85 ± 24%) against the control group (52 ± 3%), p= 0.005. The changes observed in the fibrin polymerization and lysis process of women with RM without APS and LA seem to be related to their higher fibrinogen levels, while the increased plasmin generation was related to the patients´ morbidity.

Frecuencia de fibrilación auricular y tratamiento con anticoagulantes orales en pacientes con marcapasos definitivo / Atrial fibrillation prevalence and treatment with oral anticoagulation in patients with permanent pacemakers

La fibrilación auricular (FA) es el factor de riesgo más importante para eventos tromboembólicos (ETE). El objetivo del presente estudio fue determinar la prevalencia de FA en pacientes con marcapasos definitivo (MCD), el porcentaje de anticoagulación y la prevalencia de ETE. El objetivo secundario fue determinar el nivel de conocimiento relacionado con las indicaciones de anticoagulación oral (AO) en pacientes con FA. Estudio descriptivo y retrospectivo de una serie consecutiva de pacientes. Se evaluaron factores de riesgo cardiovascular, motivos de indicación del MCD, antecedentes de FA, ETE y régimen de anticoagulación. Para determinar las potenciales causas de no AO, se realizó una encuesta a todos los médicos que habitualmente derivan sus pacientes a nuestro servicio. De 934 pacientes, el 26% (244) presentó FA, con una tasa de AO del 34%. El 77,3% presentaban un score CHADS2 ³2, solo el 2% presentó contraindicaciones para AO y la prevalencia de ETE fue del 9%. El 63% de los médicos contestó la encuesta. El 41% conocían el score CHADS2, el 33% pudo describir los parámetros clínicos que evalúa y un 23% respondieron correctamente el puntaje necesario para indicar AO. Se detectó una baja tasa de anticoagulación oral en pacientes con FA y MCD, con una elevada prevalencia de ETE y un sorprendente desconocimiento por parte de los médicos tratantes de las recomendaciones actuales de tratamiento.

Atrial Fibrillation (AF) is the most important risk factor for stroke and thromboembolic events (TE). The aims of this study were to determine the prevalence of AF among patients with permanent pacemakers (PPM), the percentage of anticoagulated patients and the prevalence on TE in this population. The secondary purpose was to determine the “level of knowledge” about indications of anticoagulation for AF patients. This was a descriptive and retrospective study on a consecutive series of patients referred for PPM implantation. Cardiovascular risk factors, indications for pacing, prior history of AF, TE and anticoagulation indication were analyzed. In order to determine possible causes for not indicating anticoagulation, an electronic survey was sent to all doctors that usually refer patients for PPM implant and follow-up to our clinic. Among 934 patients, 26% (244) presented AF of which 34% were anticoagulated. 77, 3% presented a CHADS2 score of ³2 while only 2% had absolute contraindication for anticoagulation. The prevalence of TE was 9%. More than 60% of the doctors answered the survey. More than 40% acknowledged the CHADS2 score but only 33% were able to recognize all variables included in the score and 23% were able to determine when to indicate anticoagulation properly. A low anticoagulation rate was detected among patients with AF and PPM with a high prevalence of TE and stroke. An extremely low adherence to international guidelines was detected among doctors that usually deal with this sort of patients.

Valor pronóstico de los niveles de interleucina-6 en pacientes con infarto agudo del miocardio con elevación del segmento ST / Prognostic value of serum levels of interleukin-6 in patients with ST-segment elevation acute myocardial infarction

Introducción: La interlucina-6 (IL6) participa en la aterogénesis y en el fenómeno aterotrombótico más catastrófico: el infarto agudo del miocardio con elevación del ST (IAM CEST). El objetivo de esta investigación fue evaluar el pronóstico de los niveles elevados de IL6 para eventos cardiovasculares mayores en pacientes con IAM CEST. Material y métodos: Estudiamos pacientes consecutivos con diagnóstico de IAM CEST de acuerdo con los criterios convencionales establecidos por la ACC/AHA/ESC. Se determinó IL6 sérica a las 24 horas de iniciado el evento, mediante quimioluminiscencia. Las variables de desenlace fueron arritmias, angina, falla cardiaca, reinfarto no fatal y muerte, o la combinación de ellas durante la hospitalización. Resultados: Incluimos 97 pacientes; el punto de corte de IL6 para identificar a los pacientes con alto riesgo fue de 20 pg/ml. En el grupo I (< 20 pg/ml) fueron 46 pacientes y en el grupo II (> 20 pg/ml), 51 (IL6 11.52 + 4.83 pg/ml versus 63.19 + 44.4 pg/ml, p < 0.0001). Fue más frecuente la muerte (2.2 versus 15.7 %, p = 0.023, RR 1.16 IC 95 % = 1.02-1.31) y el punto final combinado durante la hospitalización en el grupo II (21.7 versus 51 %, p = 0.003, RR = 1.59, IC 95 % = 1.16-2.19). La clase de Killip > 2 y los niveles de IL6 > 20 pg/ml fueron factores independientes para el punto final combinado. Conclusiones: Los niveles de IL6 > 20 pg/ml en IAM CEST se asociaron significativamente a más eventos cardiovasculares durante la hospitalización.

BACKGROUND: Interleukin-6 (IL6) plays a role in atherogenesis as well as in most atherothrombotic phenomenon such as ST-segment elevation acute myocardial infarction (STEAMI). Our objective was to evaluate serum levels of IL6 as prognostic value for major clinical in-hospital events in patients with STEAMI. METHODS: We studied consecutive patients with diagnosis of STEAMI according to ACC/AHA/ESC criteria. Twenty four hours after the acute event, IL6 was determined by chemiluminescence method. The major cardiovascular end points were arrhythmias, angina, heart failure, reinfarction and death. RESULTS: Included were 97 patients. The level of IL6 to identify high-risk patients was 20 pg/ml. Forty six patients had <20 pg/ml (group I), and 51 patients had >20 pg/ml (group II). Mean value of IL6 was 11.52 +/- 4.83 pg/ml vs. 63.19 +/- 44.4 pg/ml (p <0.0001). Death was more frequent (2.2 vs. 15.7%, p = 0.023, RR 1.16 95% CI 1.02-1.31) and the end point combined during hospitalization in group II was 21.7 vs. 51% (p = 0.003 RR 1.59 95% CI 1.16-2.19). Multivariate logistic regression analysis identified Killip class > or = 2 and IL6 levels > or = 20 pg/ml as predictors for in-hospital end point. CONCLUSIONS: Serum levels of IL6 >20 pg/ml in the first 24 h after STEAMI were significantly associated with higher frequency of in-hospital outcomes such as arrhythmias and death.

A patient with hypercoagulable state due to tuberculosis.

A 55-year-old male patient presented with status epilepticus following prolonged fever. Investigations revealed miliary opacities in lungs that were diagnosed as tubercular after thoracoscopic lung biopsy. Wide derangement of coagulation parameters was found, indicating a pro-coagulent state. There was evidence of widespread thrombosis.

Hipercoagulabilidade e câncer de pulmão: [revisão] / Hypercoagulability and lung cancer: [review]

A relação entre câncer e alteração na coagulação já havia sido sugerida há quase 150 anos por Trousseau e, subseqüentemente, ficou claro o maior risco que os pacientes oncológicos têm de desenvolverem fenômenos tromboembólicos. Isto pode ser conseqüência da ativação do sistema de coagulação pelas células neoplásicas ou pelas terapias empregadas (quimioterapias e cirurgias). Tais fenômenos podem, ainda, ser a primeira manifestação do câncer e a sua recorrência, mesmo com anticoagulação adequada, foi descrita. O sistema de coagulação é ativado, normalmente, com finalidade reparativa. Na presença de neoplasias, este complexo sistema está atuante frente a variados estímulos e parece contribuir para a progressão tumoral. Este efeito é mais importante para os focos metastáticos que para o próprio tumor primário. Contudo, a maior parte das vítimas de neoplasias morre das complicações das metástases, revelando a importância deste tema. Nesta área, vários mecanismos já são conhecidos e geram interessantes perspectivas para tratamentos futuros. Atualmente, o sucesso obtido com as heparinas de baixo peso molecular no carcinoma de pequenas células de pulmão é animador. Embora o conhecimento sobre esses mecanismos sejam relativamente recentes, os campos de pesquisa e tratamento estão amplamente abertos.

The relationship between cancer and coagulopathy was suggested by Trousseau nearly 150 years ago. Later, it became more evident that oncologic patients are at a higher risk of experiencing thromboembolic events. This can be due to activation of the coagulation system either by neoplastic cells or by prescribed therapies (chemotherapy or surgical procedures). In fact, these events can constitute the first manifestation of cancer, and their recurrence, despite efficient anticoagulation, has been described. The coagulation system is normally activated in order to provide healing. In the presence of neoplasms, this complex system is activated as a response to multiple stimuli and seems to contribute to cancer progression. Activation of the coagulation system has a greater effect on metastatic foci than on the primary tumor. However, most cancer victims die from complications caused by metastasis, which underscores the importance of this theme. In this area, various mechanisms have been described, creating promising perspectives for future treatments. The current success in using low-molecular-weight heparins against small cell lung cancer is encouraging. Although the knowledge of those mechanisms is relatively incipient, many basic research and clinical studies are underway.

Trastornos de coagulación en el cirrótico / Coagulation disorders in cirrhosis

The liver plays a central role in the clotting process. In this organ are sintetizated the major part of the coagulation factors. Historically, was considered that alteration in liver function causes important bleeding disorders. However, actual evidence is not in agreement with this asseveration. Decreased synthesis of clotting and inhibitor factors, decrease clearance of activated factors, quantitative and qualitative platelet defects, hyperfibrinolysis and intravascular coagulation are some of the defects observed in liver diseases. Thrombotic events, even if rare in cirrhotic patients, occur manly in the portal and mesenteric veins. The aim of the present work is to review the present evidence in coagulation disorders and liver disease.

El hígado participa de manera importante en el proceso de la coagulación. En él se sintetizan la mayor parte de los factores pro- y anticoagulantes. De manera histórica se ha considerado que las alteraciones en la función de este órgano provoca trastornos predisponentes para eventos de sangrado. La evidencia actual pone en tela de juicio esta aseveración. En los casos de hepatopatía se hacen evidentes alteraciones en el número y funcionamiento de las plaquetas, disminución de la síntesis de factores de la coagulación, disfibrinogenemia, alteraciones en la fibrinólisis, deficiencia de vitamina K y cambios similares a los ocurridos en la coagulación intravascular diseminada (CID). El presente trabajo está dirigido a revisar los conocimientos actuales respecto a las alteraciones de la coagulación presentes en los pacientes con hepatopatías.

Management of venous thromboembolism.

INTRODUCTION: Venous Thromboembolism is an important healthcare problem the world over, resulting in significant morbidity, mortality and resource expenditure. The rationale for use of thromboprophylaxis is based on solid principles and scientific evidence. Indian perspective on this topic is lacking due to the non-availability of published Indian data. This document reviews the available International and Indian data and discusses the relevance of recommendations for prevention and management of Venous Thromboembolism (VTE) in the Indian context. MATERIALS AND METHODS : Meetings of various specialists from different Indian hospitals in the field of Gastrointestinal Surgery, General and Vascular Surgery, Hematology, Intensive Care, Obstetrics and Gynecology, Oncology and Orthopedics were held in the months of August 2005 to January 2006. The guidelines published by American College of Chest Physicians (ACCP), the International Union of Angiology (IUA), and the Royal College of Obstetricians and Gynecologists (RCOG), were discussed during these meetings. The relevance of these guidelines and the practical implications of following these in a developing country like India were also discussed. Any published data from India was collected from data base searches and the results, along with personal experiences of the participating specialists were discussed. The experiences and impressions of the experts during these meetings have been included in this document. Data from recent sources (International Union of Angiology and the National Comprehensive Cancer Network (NCCN) Practice guidelines in Oncology on Venous thromboembolic disease) was subsequently also included in this document. RESULTS: The suggestions formulated in this document are practical, and would intend to serve as a useful practical reference. CONCLUSIONS: A number of unanswered questions remain in the field of thromboprophylaxis, and carefully designed research protocols may help answer some of these. Implementation of the suggestions outlined in the document remains to be studied in the Indian context.

Management of neonatal purpura fulminans with severe protein C deficiency.

Neonatal purpura fulminans is a life threatening clinical entity characterized by extensive subcutaneous thrombosis and disseminated intravascular coagulation usually manifesting shortly after birth. We report an autosomal recessive form of the disease in a neonate who was diagnosed with compound heterozygosity for mutations in his protein C gene as the molecular basis of his disorder.

Cancer related thrombophilia: clinical importance and management strategies.

Acquired thrombophilic state associated with a significant risk of thrombosis is frequently encountered in malignancy. Venous and arterial thromboembolism is a common complication and patients with cancer, also present with a hypercoagulable state, even in the absence of thrombosis. Furthermore, clotting activation may play a role in tumor progression. The pathogenesis of thrombosis in cancer is multifactorial; however, a relevant role is attributed to the tumor cell capacity to interact with and activate the host hemostatic system. Among other factors, the prothrombotic action of antitumor therapies is also important. Thrombotic events can influence the morbidity and mortality of the underlying disease. Therefore, preventing these complications in cancer patients is a clinically relevant issue. Recently, new approaches to the prevention and cure of thrombosis in cancer have been investigated, and the hypothesis that the strategies to inhibit clotting mechanism may favorably affect malignant disease is gaining increasing interest. In this article the various aspects of the complex relationship between thrombosis and cancer, from pathophysiology to therapy, are reviewed.

Activated protein C resistance and lupus anticoagulant activity induced by plasma and purified monospecific human IgG anti-β2-glycoprotein-I antibodies / Resistencia a la proteína C activada y actividad de anticoagulante lúpico inducidas por plasma y por anticuerpos purificados humanos del IgG anti β2-glicoproteína I

ABSTRACT Introduction. We investigated the activated protein C resistance (APCR) phenotype and the lupus anticoagulant (LA), activity induced by anti-β2-glycoprotein-I (anti-β2GP-I) antibodies. Patients and methods. We studied plasma and sera samples from 29 patients with persistently positive anti-β2GP-I: 22 with thrombosis (12 with primary APS, 10 with APS secondary to SLE) and seven without thrombosis (all with SLE); 25 healthy subjects were studied as controls. We detected anticardiolipin antibodies (ACA); IgG (and its subclasses) and IgM anti-β2GP-I, on irradiated and non-irradiated plates by ELISA. APCR was assessed by the activated partial thromboplastin time (APTT)-based assay and by the modified test. The FV Leiden mutation was studied by PCR. LA determination included screening and confirmatory dRVVT. Serum anti-β2GP-I were affinity purified on sepharose columns and their isotype, subclass, and reactivity against various antigens were studied by ELISA. Results. We found that titers of IgG anti-β2GP-I on irradiated plates were higher than on non-irradiated plates (p = 0.002), IgG2 was the predominant subclass. Fifteen patients (13 with thrombosis) had LA and 15 (also 13 with thrombosis) induced the APCR phenotype. Eleven (all with thrombosis) had both. Two patients were heterozygous for the Leiden mutation. Two purified antibodies, monospecific for β2GP-I, induced an in vitro APCR phenotype and LA activity. Conclusions. Our results seem to indicate that the inhibition of the APC anticoagulant function by IgG2 anti-β2GP-I with LA activity may be one of the responsible mechanisms of thrombophilia in patients with APS.

Introducción. Investigamos la resistencia a la proteína C activada (RPCA) y la actividad de anticoagulante lápico (AL), inducidas por anticuerpos anti-β2-glicoproteína-I (anti-β2GP-I). Pacientes y métodos. Estudiamos los plasmas y sueros persistentemente positivos para anti-β2GP-I de 29 pacientes: 22 tuvieron trombosis (12 con síndrome de antifosfolípidos (SAF) primario y 10 con SAF secundario a lupus erítematoso generalizado (LEG)) y siete sin trombosis (todos con LEG). Como controles estudiamos 25 sueros de personas clínicamente sanas. Detectamos anticuerpos anticardiolipina, anti-β2GP-I IgG (y sus subclases) e IgM por ELISA en placas irradiadas y no irradiadas. Evaluamos la RPCA por medio del tiempo parcial de tromboplastina activada y por la prueba modificada. Estudiamos la mutación FV de Leiden por PCR y el anticoagulante lápico con el método de dRVVT screening y confirmatorio. Después de purificar los anti-β2GP-I séricos con una columna de antígeno unido a sefarosa, analizamos por ELISA sus isotipos, subclases y reactividad contra β2GP-I y algunos fosfolípidos. Resultados. Los títulos de anti-β2GP-I IgG fueron más altos en placas irradiadas que en no irradiadas (p = 0.002), predominó la subclase IgG2. Quince plasmas (13 de pacientes con trombosis) tuvieron AL y 15 (13 también de pacientes con trombosis) indujeron el fenotipo de RPCA. Once plasmas (todos de pacientes con trombosis) indujeron ambas actividades. Dos pacientes fueron heterocigotos para la mutación de Leiden. Dos anticuerpos purificados monoespecíficos para β2GP-I indujeron el fenotipo de la RPCA y la actividad de AL in vitro. Conclusiones. Nuestros resultados sugieren que la RPCA, inducida por los anti-β2GP-I que concomitantemente tienen actividad de AL, puede tener implicaciones patogénicas en la trombofílía del SAF.

Trombofilia-estado actual / Trombofilia-current state

Introducción: Los estados de trombofilia son una tendencia especial a producir trombosis venosa, que se presentan habitualmente en personas jóvenes y a menudo son recurrentes. Sus consecuencias más trascendentes son el Tromboembolismo Pulmonar y el Síndrome Post-trombótico. Objetivos: Teniendo en cuenta las patologías de la coagulación que pueden producir estados de trombofilia en pacientes jóvenes, se evaluó la prevalencía de estos procesos en pacientes con síndrome post-trombótico severo. Lugar de aplicación: Departamento de Flebología y Linfología del Hospital Nacional de Clínicas, Córdoba. Materiales y métodos: Durante el periodo marzo de 2001 a marzo de 2002 concurrieron a la consulta flebológica 635 pacientes, de los cuales seis de ellos, 3 hombres y 3 mujeres menores de 45 años, presentaban severos trastornos del retorno venoso compatibles con cuadros postrombóticos. La edad promedio de 39 años (r: 29-45); Estos pacientes fueron estudiados mediante clínica de rutina, ecodoppler color venoso y análisis específicos de laboratorio como la Resistencia a la Proteína C activada, Proteína C, Proteína S, Anticuerpos antifosfolípidos, Antitrombina III, homocisteinemia. Resultados: Se obtuvieron valores anómalos en el perfil biológico del laboratorio en 3 pacientes; la correlación clínica y del laboratorio fue la siguiente: positivo para proteína C y Proteína S; Positivo para Anticuerpos Antifosfolípidos; y positivo para Hiperhomocisteinemia. Conclusiones: Deben preconizarse los estudios de laboratorio necesarios para descartar estados trombofilicos en pacientes menores de 45 años que presenten un primer episodio de trombosis o bien cualquier paciente que haya presentado trombosis recurrentes. Es importante resaltar que la detección temprana de estas patologías y la oportuna derivación al hematólogo, permiten establecer un tratamiento preventivo y así evitar episodios trombóticos con sus respectivas complicaciones.

Fisiopatologia e tratamento da síndrome nefrótica: conceitos atuais / Pathophysiology and treatment of nephrotic syndrome: current concepts

Foram revisados aspectos da fisiopatologia e tratamento sindrômico do estado nefrótico. São citados o conceito e as causaas de síndrome nefrótica. Foram revisados a fisiopatologia do edema, bem como as causas e otratamento do edema refratário. É apresentado um fluxograma para o manejo clínico do edema nefrótico, considerando a complexidade do edema refratário. Foram abordadas medidas para redução da proteinúria, como o uso de inibidores da enzima de conversão da angiotensina, a dieta hiporotéica e o papel dos antiinflamatórios não esteróides neste contexto. Foram revistas as complicações da síndrome nefrótica, como dislipidemia e hipercoagulabilidade no que diz respeito à sua fisiopatologia e tratamento atual

Trombofilia y embarazo / Thrombophilia and pregnancy

Las trombofilias corresponden a desordenes del sistema hemostático que predisponen a fenómenos trombóticos. Los factores de riesgo de presentar trombosis durante el embarazo están incrementados. Estudios recientes demuestran que pacientes portadoras de trombofilia tiene una alta probabilidad de presentar complicaciones durante la gestación: preeclampsia severa, retardo del crecimiento intrauterino, desprendimiento prematuro de placenta normoinserta y mortinatos. Todo esto estaría vinculado a fenómenos trombóticos de los vasos placentarios