[New oral anticoagulants: molecular characteristics, mechanisms of action, pharmacokinetics and pharmacodynamics]. / Nuevos anticoagulantes orales: características de las moléculas, mecanismos de acción, farmacocinéticas y farmacodinámicas.

The search for the ideal anticoagulant has been one of the most active research fields in medicine in the past few years. Anti-vitamin K replacement, particularly in the long term treatment of venous thromboembolism is a difficult objective to achieve due to the wide experience gathered in normal practice and low costs. But to improve the weak points of these drugs is an attractive challenge and would have a great health and social impact. It can be seen that the low molecular weight heparins, or even pentasaccharide, drugs that are already available on the market, although the have very predictable pharmacokinetics, their parenteral use, or their long half life, they are far from being ideal anticoagulants. Ximelagatran, a promising drug, a direct inhibitor of thrombin seemed to be a step forward, but the appearance of undesirable side effects led to its withdrawal. However, this line of investigation has remained open, as such that we now have data from clinical trials that back it up: the direct inhibition of thrombin and activated factor X. These two different mechanisms of action are showing promising results, in that the direct inhibitors of thrombin (dabigatran, hirudins...) are showing not to be inferior in efficacy and safety to enoxaparin in the primary prophylaxis of venous thromboembolism. Similarly, the activated factor X inhibitors (Rivaroxaban, Apixaban ) are also showing the same and in some cases, superior in its prevention. This review looks at the mechanisms of action of both pharmacological groups, their effects on haemostasis, and how they are reflected in coagulation times, their pharmacokinetics and pharmacodynamics. These new anticoagulants are nearer to the ideal anticoagulant and may, in the near future, change the panorama of anticoagulation, not only at health level, but also by achieving improved levels in the quality of life of the patients.

Nuevos anticoagulantes orales: características de las moléculas, mecanismos de acción, farmacocinéticas y farmacodinámicas / New oral anticoagulants: molecular characteristics, mechanisms of action, pharmacokinetics and pharmacodynamics

La búsqueda del anticoagulante ideal es uno de los campos de investigación más activos en los últimos años en la medicina. Sustituir a los antivitamínicos K, especialmente en los tratamientos a largo plazo por tromboembolia venosa es un objetivo difícil de alcanzar por la gran experiencia acumulada en la práctica habitual y su bajo coste, pero la mejora de los puntos débiles de estos fármacos es un objetivo atractivo y que sin duda tendrá grandes repercusiones sanitarias y sociales. Vemos que las heparinas de bajo peso molecular, o incluso el pentasacárido, son fármacos ya disponibles en el mercado que, aunque tienen una farmacocinética más predecible, su uso por vía parenteral o su larga vida media distan de ser los anticoagulantes ideales. Un paso adelante supuso el ximelagatran, fármaco prometedor, inhibidor directo de la trombina, pero la aparición de efectos indeseables aconsejó su retirada. No obstante, esta línea de investigación ha seguido abierta, de forma que ya tenemos datos aportados por ensayos clínicos que la avalan: la inhibición directa de la trombina y la inhibición directa del factor X activado. Estos dos distintos mecanismos de acción están presentando resultados prometedores, de forma que los inhibidores directos de la trombina (dabigatran, hirudinas, etc.) están demostrando no ser menos eficaces y seguros que la enoxaparina en situaciones de profilaxis primaria de la tromboembolia venosa. Igualmente, los inhibidores del factor X activado (rivaroxaban, apixaban¿) también están demostrando lo mismo y en algún caso superioridad en su prevención. En esta revisión se repasan los mecanismos de acción de ambos grupos farmacológicos, sus efectos en la hemostasia y cómo se reflejan en los tiempos de coagulación su farmacocinética y su farmacodinamia. Estos nuevos anticoagulantes se aproximan más al anticoagulante ideal y en un futuro próximo pueden cambiar el panorama de la anticoagulación no sólo en el ámbito sanitario, sino también en conseguir cotas de mejora de la calidad de vida de los pacientes

The search for the ideal anticoagulant has been one of the most active research fields in medicine in the past few years. Anti-vitamin K replacement, particularly in the long term treatment of venous thromboembolismis a difficult objective to achieve due to the wide experience gathered in normal practice and low costs. But to improve the weak points of these drugs is an attractive challenge and would have a great health and social impact. It can be seen that the low molecularweight heparins, or even pentasaccharide, drugs that are already available on the market, although the have very predictable pharmacokinetics, their parenteral use, or their long half life, they are far from being ideal anticoagulants. Ximelagatran, a promising drug, a directinhibitor of thrombin seemed to be a step forward, but the appearance of undesirable side effects led to its withdrawal. However, this line of investigation has remained open, as such that we now have data from clinical trials that back it up: the direct inhibition of thrombin and activated factor X. These two different mechanisms of action are showing promising results, in that the direct inhibitors of thrombin (dabigatran, hirudins...) are showing not to be inferior in efficacyand safety to enoxaparin in the primary prophylaxis of venous thromboembolism. Similarly, the activated factor X inhibitors (Rivaroxaban, Apixaban …) are also showing the same and in some cases, superior in its prevention. This review looks at the mechanisms of action ofboth pharmacological groups, their effects on haemostasis, and how they are reflected in coagulation times, their pharmacokinetics and pharmacodynamics. These new anticoagulants are nearer to the idealanticoagulant and may, in the near future, change the panorama of anticoagulation, not only at health level, but also by achieving improved levels in the quality of life of the patients

[Pure red cell aplasia in a lung transplant patient]. / Aplasia pura de células rojas en un paciente trasplantado pulmonar.

Aplastic anemia secondary to infection by parvovirus B19 is normally an extremely rare problem in patients with no prior history. However, the presence of certain risks, such as receiving chronic immunosuppressant therapy, may facilitate its appearance. Very few cases have been published concerning red cell aplasia due to parvovirus B19 infection in patients receiving a transplanted lung. We report the case of a 24-year-old woman with cystic fibrosis who had received a double lung transplant. The patient developed red cell aplasia secondary to parvovirus B19 infection; severe anemia requiring multiple transfusions. Five days of intravenous immunoglobulin therapy resolved the anemia. We discuss the difficulty of serological diagnosis in such cases, the importance of using techniques that identify the virus and taking measures that may prevent recurrence.

Aplasia pura de células rojas en un paciente trasplantado pulmonar / Pure red cell aplasia in a lung transplant patient

La anemia aplásica aguda secundaria a la infección por Parvovirus B19 suele ser un problema extremadamente raro en sujetos sin patología previa. Sin embargo, la existencia de determinadas situaciones de riesgo, como recibir terapia inmunosupresora de forma crónica, puede facilitar su aparición. Son muy escasos los casos que se han publicado hasta el momento de aplasia de células rojas debido a infección por Parvovirus B19 en pacientes sometidos a trasplante pulmonar. Se presenta el caso de una mujer de 24 años de edad trasplantada bipulmonar por una fibrosis quística, que desarrolló una aplasia de células rojas, condicionante de una anemia grave que requirió transfusiones múltiples, secundaria a una infección aguda por Parvovirus B19. Un tratamiento con inmunoglobulinas intravenosas durante 5 días permitió la resolución de la anemia. Se discute la dificultad del diagnóstico serológico en estos casos y la importancia del uso de las técnicas de identificación viral para lograrlo, y se argumentan las posibles medidas preventivas para evitar su recurrencia (AU)

Autoimmune thrombocytopenia associated with hepatitis C virus infection.

We have retrospectively analyzed a series of 19 patients with hepatitis C virus (HCV) infection and chronic thrombocytopenia not attributable to hypersplenism or to other causes. Antiplatelet antibodies were present in 81% of cases. Response to prednisone was observed in 6 of 7 patients and 1 of 3 patients responded to intravenous immunoglobulins. No case of reactivation of liver disease was observed during or after therapy. We consider that the possibility of an underlying mechanism should be evaluated in thrombocytopenic patients with HCV infection who do not present hypersplenism. These patients could benefit from steroid treatment.

bcl-2 expression in plasma cells from neoplastic gammopathies and reactive plasmacytosis: a comparative study.

BACKGROUND AND OBJECTIVE: bcl-2 oncoprotein plays a major physiological role in hemopoietic and non-hemopoietic cells by preventing apoptosis (programmed cell death). Disregulation of this process may be important in oncogenesis and the response to treatment of patients with different hematological malignancies. We have investigated the levels of bcl-2 expression in plasma cells from patients with reactive plasmacytosis (RP), monoclonal gammopathy of unknown significance (MGUS) and multiple myeloma (MM), correlating the bcl-2 expression and clinico-biological features in MM patients. DESIGN AND METHODS: The percentage of bcl-2 (+) plasma cells and levels of bcl-2 protein expression were investigated in 73 patients at diagnosis. Immunofluorescence and immunoenzymatic methods were applied using McAb against bcl-2 protein, and the intensity of protein expression was assessed by both the mean channel fluorescence intensity (MFI) and semiquantitative methods. To evaluate the intensity of bcl-2 expression in proliferating plasma cells, sequential double immunoenzymatic staining with McAb Ki-67 and bcl-2 was applied in 10 patients with MM. Correlations between bcl-2 expression and the clinico-biological features in MM patients were also studied. RESULTS: The proportion of bcl-2 (+) plasma cells was significantly higher in MGUS and MM than in RP (p < 0.001). The intensity of bcl-2 expression in plasma cells (assessed by MFI) was significantly different between all groups studied (p < 0.0001). RP showed lower expression than MGUS and MM patients. MM stage III patients demonstrated higher bcl-2 expression values than MGUS (p < 0.01). According to the proportion of plasma cells expressing Ki-67, patients with a proliferative index (Ki-67+) > 4% showed lower bcl-2 expression than patients with proliferative index < 4% (p < 0.05). Immunocytochemistry showed that plasma cells from RP had a lower intensity of bcl-2 expression than MM (p < 0.001), and double immunostaining Ki-67/bcl-2 demonstrated that the majority of proliferating plasma cells had weak bcl-2 expression. There was no correlation between bcl-2 expression and clinico-biological parameters, response to therapy or overall survival in MM patients. INTERPRETATION AND CONCLUSIONS: Globally, the number of bcl-2 (+) plasma cells and the intensity of protein expression in neoplastic gammopathies are significantly higher than in reactive plasmacytosis and bcl-2 levels tend to increase with disease stage. bcl-2 may be relevant to the pathogenesis of malignant gammopathies, prolonging the survival of plasma cells by preventing apoptosis and increasing the chance of acquiring additional gene defects. bcl-2 expression could also contribute to the resistance to chemotherapy observed in MM disease.

Sezary cell-like leukemia with atypical immunophenotype.

We describe the clinical and laboratory features of an unusual case with Sezary cell-like leukemia. Clinical manifestations were: anemia (Hb 9.4 g/dl), severe thrombocytopenia (5 x 10(9)/l), lymphocytosis (43 x 10(9)/l) and splenomegaly. There was no lymphadenopathy, hepatomegaly or skin lesions. Bone marrow trephine showed diffuse infiltration by atypical lymphoid cells. By ultrastructural analysis the cells were small to medium-size lymphocytes with nuclear features identical to Sezary cells. Immunophenotyping showed that most peripheral blood mononuclear cells were negative with B lymphoid, myeloid, and stem cell-associated markers and were also negative with most T lymphoid markers (CD2, CD4, membrane/cytoplasmic CD3, CD5 and CD8). However, they were positive with CD38 (70%), CD7 (25%) and TIA-2 (25%). Molecular analysis showed a clonal rearrangement of the TCR beta and gamma chain genes. The patient was initially treated with vincristine, doxorubicin and asparaginase and then with six cycles of CHOP, achieving a complete remission and remaining free of disease 22 months from diagnosis. Aberrant immunophenotypes are not frequent in primary T cell leukemias. This is the first case of a rare type of T cell neoplasm, Sezary cell-like leukemia, in which cells lacked most of the T cell-associated antigens.

Circulating Ki67 positive lymphocytes in multiple myeloma and benign monoclonal gammopathy.

AIMS: To estimate the proportion and nature of the proliferating (Ki67+) circulating lymphocytes in a series of patients with multiple myeloma and monoclonal gammopathy of unknown significance (MGUS) and to correlate this with other clinical and laboratory parameters, using blood from healthy adults as a control. To investigate the extent to which the B and T lymphoid components are involved in progression and/or control of disease. METHODS: Blood lymphocytes from 15 patients with multiple myeloma, 10 patients with MGUS and 10 healthy adults were analysed using a sequential double immunoenzymatic staining technique. Antibodies directed against Ki67 were used to detect cells in cycle, CD3, CD4, and CD8 to identify T cells, HLA-Dr as a marker for B cells and activated T cells, and CD11b as a marker for natural killer cells. Polyclonal antibodies directed against the kappa and lambda immunoglobulin light chains were also used to detect B cells. RESULTS: The proportion of proliferating (Ki67+) lymphocytes was significantly higher in patients with multiple myeloma (6.8 +/- 2.6) and MGUS (3.5 +/- 1.1) compared with the normal controls (1.69 +/- 0.3); this was also true when multiple myeloma and MGUS cases were compared. In multiple myeloma and MGUS over 50% of the Ki67+ cells were activated T lymphocytes (CD3+/HLA-Dr+); a minority (11%) were non-clonal B lymphocytes. In contrast to controls (6.7 +/- 1.9), in patients with multiple myeloma and MGUS the proportion of proliferating T cells expressing CD8 (23.6 +/- 12.5 and 15.3 +/- 7.7, respectively) and CD11b (13 +/- 8.7 and 11.6 +/- 3.9, respectively) was higher. In multiple myeloma there was a positive correlation between the proportion of Ki67+ lymphocytes, beta-2-microglobulin concentrations and disease stage. CONCLUSIONS: Although the number of patients investigated is small, this study suggests that Ki67 expression in blood lymphocytes from patients with multiple myeloma may be a good prognostic indicator for aggressive disease and may help to distinguish multiple myeloma from MGUS. The activated proliferating T cells in these diseases may represent an immunological reaction against the tumour.