Hipercoagulabilidad en fibrilación auricular y su relación con factores de riesgo para embolia sistémica / Hypercoagulable state in atrial fibrillation and its relationship with risk factors for systemic embolism

Background: Atrial fibrillation is associated to a high risk of systemic embolism and to hypercoagulability. Aim: To evaluate the activation of the coagulation cascade through determinations of the thrombin-antithrombin complex in patients with atrial fibrillation and to correlate this data with the clinical and echocardiographic risk factors for systemic embolism. Patients and Methods: In 53 patients with atrial fibrillation plasma levels of the thrombin-antithrombin complex were determined on admission to a coronary care unit and 30 days later. Using a univariate and multiple regression analysis, the association basal thrombin-antithrombin with the duration of the arrhythmia, age over 70 years, previous use of antiplatelet agents, history of hypertension, mitral valve disease, diabetes, heart failure, previous systemic embolism, left atrial diameter and the presence of spontaneous contrast echo or thrombus in the left atrial appendage, was studied. Results: Basal thrombin-antithrombin values were 40.1ñ69 mg/L (Median 8.34 [3.0-47.5]) compared to 2.7ñ3.3 mg/L in healthy controls (p <0.001). No significant correlation was found between activation of the coagulation cascade and risk factors for systemic embolism. There were no significant differences in thrombin-antithrombin values between patients with chronic or paroxysmal atrial fibrillation (29.5ñ43 mg/L and 49.4ñ83 mg/L respectively). Mean thrombin-antithrombin values in patients under antiplatelet agents were lower than in those without treatment (17.3ñ43 vs 66.8ñ127 mg/L; p=0.018). Conclusions: The activation of the coagulation cascade in patients with atrial fibrillation was confirmed. However, no association of this activation with well known clinical and echocardiographic risk factors for systemic embolism, was found. Previous antiplatelet treatment prevented a higher activation of the coagulation cascade

Trasplante de médula ósea en pacientes pediátricos / Paediatric bone marrow transplantation

Objetivo: el transplante de médula ósea (TMO) es un procedimiento que constituye la única posibilidad de tratamiento para algunas enfermedades hematológicas y oncológicas de la infancia. Se describe un programa de trasplante de médula ósea implementado en nuestra institución, habilitando la infraestructura y personal necesarios. Pacientes: 60 pacientes pediátricos han recibido TMO, 37 niños, 23 niñas, edades entre 7 meses y 17 años. Los diagnósticos correspondieron a leucemia aguda 24, aplasia medular 5, leucemia mieloide crónica/mielodisplasia 6, tumores sólidos 17, enfermedades congénitas 7, histiocitosis 1. Fueron TMO autólogos 14 casos y alogeneicos 46. Donantes: hermanos idénticos: 34. Familiares no idénticos: 6. Cordón umbilical no relacionado: 6. Correspondieron a grupo de riesgo estándar 31 pacientes, y grupo de riesgo alto (leucemias o tumores refractarios, pacientes politransfundidos, donantes no hermano), 29. Resultados: sobrevida actuarial libre de eventos (a 3 años): grupo total: 36 por ciento, grupo riesgo estándar: 61 por ciento, grupo riesgo alto: 10 por ciento (p < 0,01). Conclusiones el TMO es un tratamiento efectivo para pacientes pediátricos sin otra alternativa terapéutica. Los resultados en pacientes con enfermedad muy avanzada son malos, apoyando la necesidad de realizar oportunamente el procedimiento

Células y órganos del sistema inmune / Cells and organs of the immune system

Las células del sistema inmune que incluyen linfocitos, granulocitos y monocitos-macrófagos, se forman en la médula ósea a partir de células pluripotentes, a través de un proceso finamente regulado y el que participan varias citoquinas. Los granulocitos (neutrófilos, eosinófilos y basófilos) presentan particularidades morfológicas y funcionales. La principal función de los neutrófilos es su capacidad fagocítica. En el capítulo se explican los procesos de activación, quimiotaxis, fagocitosis y bacteriolisis. Las células del sistema fagocítico mononuclear (monocitos y macrófagos) tienen como función fagocitar; actividad más desarrollada en los macrófagos, que son células tisulares derivadas de los monocitos circulantes. Los linfocitos son las células que participan en la inmunidad adquirida o específica. Las células T participan en la inmunidad celular y las células B en la inmunidad humoral. Una tercera subpoblación de linfocitos, las células NK, participan en la inmunidad celular de tipo innata. Los órganos linfoides se pueden clasificar en primarios (timo y médula ósea) y secundarios (bazo, ganglios linfáticos y tejido linfoide asociado a mucosas). En el timo maduran los LT y en la médula ósea los LB. En los órganos linfoides secundarios los linfocitos y otras células del sistema inmune toman contacto con los antígenos y es en ellos donde se genera la respuesta inmune específica. En estos órganos existen zonas ricas en células T, y otras en que, principalmente, existen células B. La capacidad de los linfocitos de recircular entre los órganos linfoides secundarios, vasos linfáticos, conducto torácico y vasos sanguíneos le permiten tomar contacto con antígenos en diferentes lugares del organismo

Aloinmunización transplacentaria por antígenos plaquetarios específicos: prevalencia y características en una población chilena / Transplacental alloimmunization against platelet antigens: prevalence and features in a chilean population

Backgrour: Neonatal alloimmune thrombocytopenia (NAIT) is a result of fetomaternal incompatibility. Platelet destruction is caused by a maternal alntibody directed against a fetal platelet antigen inherited from the father and lacking on the mother's platelets. The incidence and features of transplacental alloimmunization depend on the frequency of expression of platelet specific antigens, which are highly variable among different populations. Aim: To determine the prevalence and characteristics of transplacental alloimmunization in a large, group of pregnant women in Chile. Material and methods: We, studied 3,041 samples obtained during the third trimester of gestation. In all samples, anti platelet antibodies were screened by ELISA with platelet membranes fixed to a microtiter plate. Positive samples were further studied for antigenic specificity with the monoclonal antibody specific immobilization of platelet antigens (MAIPA) test. Results: Anti platelet antibodies were found in 261 samples (8.5 percent). The MAIPA test identified 6 samples with antibodies directed against major platelet membrane glycoproteins, 2 anti GPIb, 2 anti GPIIb/IIIa and 2 anti GPIa/IIIa. In four cases, anti HLA antibodies coexisted. Two cases corresponded to well defined platelet antigen systems: one anti HPA-1a and one anti HPA-5b. No clinical evidence of thrombocytopenia of the newborn was detected in all these cases with anti GP antibodies. Conclusions: A prevalence of platelet specific antibodies of 0.2 por ciento with only one anti HPA-1a was detected. These findings are in contrast with those of other populations but in accordance with the low frequency of the HPA-1b/b phenotype in the Chilean population. The very low incidence of platelet specific antibodies and the lack of association with clinical thrombocytopenia in the newborn, do not support the recommendation of routine antenatal screening to all women in Chile

Aloinmunización plaquetaria en pacientes onco-hematológicos politransfundidos: estudio prospectivo en adultos y niños / Platelet alloimmunization in patients with multiple transfusions. Prospective study in adults and children

Background: Refractoriness continues to he a major complication of platelet transfusion therapy in patients with multiple transfusions: Despite most cases are secondary to non-immune causes, the most serious is that associated to alloimmunization. The incidence and consequences of HLA and non-HLA (platelet specific) antibodies are unknown in our country. Aim: To prospectively determinate the frequency and characteristic of post transfusion alloimmunization and the incidence of platelet specific antibodies. Patients and methods: Forty one adults and 24 children with a recently diagnosed malignancy and undergoing chemotherapy that required multiple transfusions were studied. Screening for antiplatelet antibodies (platelet membrane ELISA) was performed before the first transfusion, every four weeks or whenever the 1 hour corrected count increment for platelet transfusions was lower that 5000. Platelet specific antibodies werw identified with a monoclonal antibody-specific immobilization of platelet antigens (MAIPA), with anti-GPIIb, GPIIb/IIIa, GPIa/lia and anti-HLA class I. Results: Adult patients received an averafge of 10.2 ñ 5.5 units of red blood cells and 58.6 ñ 35.4 units of platelets. Children received 4.8 ñ 3.7 units of red blood cells and 9.6 ñ 6.7 units of platelets. HLA antibodies appeared in 7 of 41 adult patients (17 percent), platelet specific alloantibodies were found in two patients (one anti GP Ia/IIa and one anti GP ib). Platelet refractoriness appeared in three alloimmunized patients. No Child had detectable serum antibodies during follow up. Conclusions: Platel transfusion refractoriness of immune origin occurs infrequently in our population and the presence of platelet antibodies does not mean that it will appear. The use of leukocyte depleted blood components to prevent refractoriness cannot be justified at this time

Hemorragias mucocutáneas: evaluación clínica, secuencia de estudio y frecuencia relativa de enfermedades hereditarias de la hemostasia en población chilena / Mucocutaneous hemorrhages: clinical evaluation, study sequency and related frequency of hemostatic hereditary disases in Chilean population

Patients and methods: Five hundred eighty nine patients whose main symptom was the presence of mucocutaneous hemorrhages were studied. Bleeding time, platelet count, coagulant activity of factor VIII (FVIII:C), FvW: Ag and FvW:CoRis and ABO blood group were measured in all patients in a first stage. According to the results of these tests, further studies were decided. Results: In patients younger than 13 years old, males predominated and, in older patients, females consulted with higher frequency. There was a higher proportion of individuals with O blood type than in the normal population. Bleeding time was abnormal in 330 patients (56 percent). One hundred ten patients (19 percent) had von Willebrand disease and, among them, one third had a normal bleeding time. Isolated reduction of factor VIII activity was found in 66 patients (11 percent, 51 males) and 32 of these had normal bleeding time. Eighty one patients (14 percent) were considered to have an hereditary platelet function defect. A precise diagnosis was not achieved in 332 patients (56 percent). Conclusions: Among patients consulting for mucocutaneous hemorrhages, 19 percent had von Willebrand disease, 11 had an isolated reduction of factor VIII activity, 14 percent had platelet function defects and in 56 percent, a precise diagnosis was not reached

Hematoma intracerebral como primera manifestación de hemofilia / Intracranial hematoma as the first manifestation of hemophilia

La hemorragia intracraneana ocurre entre 2 por ciento y 13 por ciento de los enfermos hemofílicos,pudiendo ser subaracnoidea, subdural o intracerebral (hematoma intracerebral). Es infrecuente como primera manifestación de la enfermedad, habiéndose demostrado en 5,9 por ciento de los pacientes con hemofilia A. En 54 por ciento de los casos hay antecedentes de traumatismo, pero en 38 por ciento no se identifica una causa desencadenante. La tomografía axial computadorizada suele permitir el diagnóstico sin dificultad, pero excepcionalmente las imágenes obtenidas pueden ser confundidadas con las de otras afecciones. Se describe un niño de tres meses de edad, en quien la primera manifestación de hemofilia fue un hematoma intracerebral, interpretado inicialmente como tumor, descubriéndose su verdadera naturaleza durante la intervención quirúrgica y su etiología hemofílica al estudiar la coagulación como consecuencia de nuevos sangramientos intracraneanos en el período postoperatorio

Hemofilia A: análisis de intron 18 e intron 7 del gen del factor VIII y su rol en una estrategia de diagnóstico de portadoras en una población chilena / Hemophilia A: analysis of intron 18 and intron 7 of factor VIII gene and its role in a strategy of carrier diagnosis in a chilean population

Hemophilia A is an X-linked disorder of coagulation caused by a deficiency of factor VIII. A large number of different mutations in the VIII gene have been identified. Thus, the detection of female carriers, depends upon the analysis of DNA polymorphism in and near the factor VIII gene. Our aim was to develop a strategy, earlier reported, for carrier testing in families at risk of hemophilia A. In this study, we analyzed the DNA polymorphisms in 26 affected families, with use of the factor VIII intragenic polymorphisms identified by the restriction enzymes Bcll and AlwNI and by differential hybridization with sequence-specific oligonuclaotide probes recognizing Bcll and AlwNI polymorphisms. While the DNA polymorphism detected by Bcll site in intron 18 of the factor VIII gene was informative for 30 percent families studied, the AlwNI/intron 7 polymorphism provided aditional information (4 percent). The carrier status of the remaining 58 percent could be determined utilizing the other polymorphisms suggested the strategy. The 2 polymorphic sites used combined with the other polymorphisms, intragenic and extragenic, can generate levels of informativeness greater than 98 percent. We concluded that the strategy for carrier testing would be a good alternative in genetic counselling for hemophilia A., but its limitations must be carefully taken into account

Resistencia a la proteína C activada: estudio de laboratorio y prevalencia del defecto en la población chilena / Activated protein C resistance: laboratory study and prevalence of the defect in chilean population

Activated protein C resistance (APCR) or factor V leiden has been recently described as the most prevalent hemostatic abnormality associated with venous thrombosis. In patients with familial thrombophilia, the prevalence of APCR is 19-60 percent and around 20 percent in sporadic venous thrombosis. APCR is usually measured by the degree of prolongation of activated Partial Thromboplastin Time (APTT) on patient's plasma, induced by addition of APC in comparison to normal plasma. At the molecular level the defect is caused by a single-point mutation in the gene for factor V (FV) (G1.691-A), that predict the replacement of Arg506 by Glutamine. This mutation makes activated factor V resistant to inactivation by APC. Since the prevalence of the defect is highly variable among different populations, the objective of this work was to study its frequency in our population and in patients with thrombophilia. We defined the normal range for APTT ratio (APTT+APC/APTT-APC) in a group of 73 healthy volunteers in whom the presence of FV Q506 mutation was searched using Mnll enzyme digestion of PCR amplified genomic fragment containing the nucleotide 1.691. The lower limit of APTT ratio stablished in this group was 2.13. APCR was found in 6 out of 159 control subjects (3.8 percent) and in 14/50 (28 percent) of patients with thrombosis. In 13 cases as a single defect and in 1 associated to type I protein C deficiency. All the APCR patients and control subjects were heterozygotes by gene analysis. The results demonstrate that in our population APCR is also the most common defect associated with thrombosis, in accordance with a high prevalence in the population. The ability to screen for this defect will permit the identification of carriers that would benefit preventive therapy at risk situations

Trasplante de médula ósea en el tratamiento de enfermedades hematológicas malignas / Allogenic bone marrow transplantation in patients with malignant hematological diseases

We have treated 28 patients (pts) with malignant hematological diseases with allogenic bone marrow transplantation (BMT). 18 pts had acute lymphoblastic (ALL) and non lymphoblastic leukemia (ANLL), 5 chronic myeloid leukemia (CML), 2 severe aplastic anemia (SAA), 1 myelodisplasia, 1 Fanconi's anemia and 1 advanced Non Hodgkin's lymphoma. All but three received the graft from HLA identical sibling donors. We used conditioning with total body irradiation and chemotherapy (cyclophosphamide, cytarabine and etoposide) in 17 pts and chemotherapy alone in 11.24 pts had a full hematological recovery 18 to 25 days post BMT. 15 pts died after BMT as a consequence of toxicity or early infection (4), graft failure (2), graft vesus host disease (4) or relapse (5). Actuarial event free survival for the group with favorable prognosis (SAA, ALL and ANLL in first or second remission and CML in chronic phase) is 57 percent at 36 months. Allogeneic BMT is an effective and feasing therapeutic procedure for selected patients with hematological malignancies