Trombocitopenia inducida por heparina: Nuevas opciones terapéuticas / Heparin-induced thrombocytopenia. New therapeutical options

La trombocitopenia inducida por heparina (TIH) es una reacción adversa inmunológica mediada por la formación de anticuerpos contra el complejo heparina-factor plaquetario 4 (FP4), caracterizada por la presencia de trombocitopenia y la asociación paradojal de trombosis arterial o venosa. Es una complicación poco frecuente pero grave del uso de cualquier tipo de heparina. En tratados con procedimientos cardiovasculares como intervención coronaria percutánea y cirugía de revascularización cardiaca, la prevalencia de anticuerpos es significativamente mayor que en otros escenarios clínicos. El reconocimiento de las características clínicas y de laboratorio permite la suspensión inmediata de la heparina y la instauración de tratamiento anticoagulante alternativo, para evitar la progresión y formación de nuevos trombos y sus complicaciones. En la presente revisión se resumen las diferentes alternativas terapéuticas para la TIH, en particular los anticoagulantes orales directos (DOACS) como el dabigatran, rivaroxaban y apixaban que pueden proporcionar una nueva opción para el tratamiento de TIH.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse reaction due to antibodies to a multimolecular complex of heparin and platelet factor 4 (PF4) characterized by moderate thrombocytopenia and paradoxical arterial or venous thrombosis. It is a relatively infrequent complication related to the administration of any type of heparin. In patients undergoing percutaneous coronary revascularization or coronary artery by-pass graft the prevalence of HIT is higher than in other clinical settings. Recognizing clinical and laboratory features of HIT allow immediate discontinuation of heparin and the use of alternative anticoagulants to avoid serious thrombotic complications. In this review, we summarize different therapeutic options for the treatment of HIT with special emphasis on direct oral anticoagulants (DOACS) such as dabigatran, rivaroxaban and apixaban. DOACS might represent a therapeutic alternative for HIT treatment.

Randomized clinical trial of human interleukin-11 in dengue fever-associated thrombocytopenia

To assess the effectiveness of recombinant human [rh] IL-11 to increase platelets count in patients suffering from Dengue fever [DF]. Randomized double blind placebo control study. Farooq Hospital, Lahore, from July to October 2011. Forty hospitalized patients suffering from Dengue fever having platelets count A[2] 30000 per micro liter were randomly categorized into two groups, rhIL-11 [test] and distilled water [placebo] groups. The efficacy outcomes [as indicated by step up in platelets count at 48 hours] for the treatment group were compared with the outcomes for the placebo group. The data revealed that the increase in platelet response with recombinant human interleukin 11, 1.5 mg subcutaneously is significantly more brisk than the placebo group. The platelets response in patients with severe thrombocytopenia was greater in the treatment group [50%] at 48 hours as compared to the placebo group [20%] [p=0.047]. Response rate was slightly greater among males [6/10, 60%] than females [8/16, 50%]; moreover, three-fourth [75%] female responders were in the placebo group, compared to half [50%] male responders in the treatment group. Results of the study suggest that treatment of severe thrombocytopenia accompanying DF with recombinant human interleukin11 may be a useful therapeutic option

Heparin-induced thrombocytopenia: a review of concepts regarding a dangerous adverse drug reaction / Trombocitopenia induzida por heparina: revisão de conceitos de uma importante reação adversa a medicamentos

Heparin is a natural agent with antithrombotic action, commercially available for therapeutic use as unfractionated heparin and low molecular weight heparin. Heparin-induced thrombocytopenia (HIT) is a serious adverse reaction to heparin that promotes antibodymediated platelet activation. HIT is defined as a relative reduction in platelet count of 50% (even when the platelet count at its lowest level is above > 150 x 10(9)/L) occurring within five to 14 days after initiation of the therapy. Thrombocytopenia is the main feature that directs the clinical suspicion of the reaction and the increased risk of thromboembolic complications is the most important and paradoxical consequence. The diagnosis is a delicate issue, and requires a combination of clinical probability and laboratory tests for the detection of platelet activation induced by HIT antibodies. The absolute risk of HIT has been estimated between 1% and 5% under treatment with unfractionated heparin, and less than 1% with low molecular weight heparin. However, high-quality evidence about the risk of HIT from randomized clinical trials is scarce. In addition, information on the frequency of HIT in developing countries is not widely available. This review aims to provide a better understanding of the key features of this reaction and updated information on its frequency to health professionals and other interested parties. Knowledge, familiarity, and access to therapeutic options for the treatment of this adverse reaction are mandatory to minimize the associated risks, improving patient safety.

A heparina é um agente natural com ação antitrombótica, sendo disponibilizadas para uso terapêutico a heparina não fracionadaeaheparina de baixo peso molecular. A trombocitopenia induzida por heparina (TIH) é uma reação adversa grave às heparinas mediada por anticorpos que promovem ativação de plaquetas. A TIH é definida como uma redução rela- tiva na contagem de plaquetas de 50% (mesmo se a contagem de plaquetas no seu nível mais baixo estiver acima 150 x 10(9)/L) que pode ocorrer no período de cinco a 14 dias após o início da terapia com o medicamento. A trombocitopenia é a principal característica que direciona a suspeita clínica da reação, sendo o aumento do risco de complicações tromboembólicas a consequência mais importante e paradoxal. O diagnóstico é uma questão delicada e requer a combinação da probabilidade clínica com testes laboratoriais para detectar a ativação plaquetária induzida pelos anticorpos da TIH. O risco absoluto de TIH tem sido estimado entre 1 e 5% no tratamento com heparina não fracionada e inferior a 1% no uso de heparina de baixo peso molecular. No entanto, evidências de alta qualidade provenientes de ensaios clínicos randomizados sobre a frequência dessa reação são escassas. Além disso, informações sobre a frequência de TIH em países em desenvolvimento não são amplamente disponíveis. Esta revisão teve como objetivo fornecer aos profissionais de saúde e demais interessados um melhor conhecimento sobre a TIH e as principais características dessa reação, bem como apresentar dados atualizados sobre a frequência da mesma. Conhecimento, familiaridade e acesso a opções terapêuticas para o tratamento dessa reação adversa são necessários para minimizar os riscos associados, melhorando a segurança do paciente.

Prevalencia de trombocitopenia en niños con HIV/sida / Prevalence of thrombocytopenia in HIV infected children

La trombocitopenia es una de las múltiples alteraciones hematológicas presentes en pacientes infectados con el virus de la inmunodeficiencia humana (HIV). Puede ser de curso crónico, en la cual la destrucción inmune, el secuestro esplénico o el daño en la producción son los mecanismos primariamente involucrados, o aguda, acompañando a otra intercurrencia. En este trabajo se evaluó la prevalencia de trombocitopenia en un lapso de 14 años, en una población pediátrica con HIV/sida, analizando las características clínicas y la relación con el estado inmuno-virológico. La prevalencia de trombocitopenia fue de 8.5%, (29 de los 339 niños en seguimiento). En 22 fue de curso crónico y en 7 aguda. Los pacientes evaluados presentaron niveles porcentuales de TCD4+ variables y la presencia de trombocitopenia no estuvo en relación con el compromiso inmunitario. Los pacientes trombocitopénicos tuvieron niveles de carga viral significativamente mayores que los que no la presentaron. En 10 de los 29 niños con recuentos plaquetarios disminuidos, la trombocitopenia fue la manifestación inicial de la infección por HIV. Las manifestaciones hemorrágicas de las trombocitopenias crónicas fueron leves, presentes en el 23% de los niños y no se asociaron al deterioro inmunológico, mientras que en las agudas fueron más graves y condicionadas a la evolución de la enfermedad coexistente. El desarrollo de trombocitopenias se ve favorecido por la continua actividad viral y la falla en la implementación del tratamiento antirretroviral adecuado.

Thrombocytopenia is a common hematologic finding in patients infected with the human immunodeficiency virus. Multiple mechanisms may contribute to the development of chronic thrombocytopenia as immune-mediated platelet destruction, enhanced platelet splenic sequestration and impaired platelet production. Acute thrombocytopenia is frequently associated with coexisting disorders. In this study, the prevalence of thrombocytopenia was evaluated in a cohort of HIV infected children analyzing the clinical features and the association with the immunological and virological status of the disease in a 14 year-follow-up period. Thrombocytopenia prevalence was of 8.5% (29 out 339 children evaluated). Chronic and acute thrombocytopenia was observed in 22 and 7 children respectively. The percentages of CD4+ T cells were variable and not related with the presence of thrombocytopenia. Thrombocytopenic patients showed viral load levels significantly increased; being the thrombocytopenia the initial clinical manifestation of HIV infection in 10 out 29 children. Mild chronic thrombocytopenia bleeding found in 23% of children evaluated was not correlated with the immunologic status of the disease. In contrast, the severity of acute thrombocytopenia depended on the evolution of associated clinical conditions. Constant viral activity and failure in the use of antiretroviral agents might induce the development of thrombocytopenia in HIV-infected children.

Steroid responsive prolonged thrombocytopenia in dengue.

Prolonged thrombocytopenia in a usual case of dengue virus infection is uncommon. Dengue-related thrombocytopenia is self-limiting and responds within 3-5 days. An underlying immunological disorder may be responsible for delayed return of platelet count to a normal level. We present a case of prolonged thrombocytopenia in a case of dengue hemorrhagic fever. The response to steroids suggests a possible immunological dysfunction.

Consecuencias del dengue hemorrágico en niños / Impact of dengue hemorrhagic fever in children

En los niños, el dengue se presenta con una variabilidad sintomática caracterizado por manifestaciones de extravasación vascular que pueden conllevar a consecuencias severas en términos de mortalidad y de costos. Estudio prospectivo y descriptivo realizado en Pediatría Médica Infecciosa (PMI) del hospital Universitario de Caracas (HUC), en niños de un mes a 12 años, con criterios de dengue hemorrágico (DH) y evidencia por laboratorio de infección aguda o reciente, que ingresaron entre enero 2000 y junio 2008, con el objetivo de evaluar las consecuencias en términos de mortalidad y costos por hospitalización. De 4 386/930 hospitalizados que ingresaron con diagnóstico de dengue, 453 cumplieron con los criterios de inclusión representando el 10 por ciento de las hospitalizaciones en PMI. El DH se presentó con mayor frecuencia entre los 5 y 9 años de edad y en el segundo semestre de cada año. El promedio de hospitalización fue de 6 días. Las consecuencias se evaluaron en términos de pérdidas de vidas (3 niños), con una tasa de letalidad 0,6 por ciento y egresos monetarios por concepto de hospitalización (exceptuando de la definición, costos/medicamentos y pruebas de laboratorio). Los gastos/hospitalización/día oscilaron entre 100 y 350$. Un 15 por ciento de los pacientes recibieron antibióticos por diagnósticos diferenciales. Ha habido un incremento progresivo de hospitalizaciones por DH en PMI, desde el 2000, predominando en la época de lluvia, con registros de casos fatales. Se generaron costos hospitalarios elevados por hospitalización que pudieran ser derivados a campañas de prevención.

Coagulopathy in dengue infection and the role of interleukin-6.

Interleukin-6 (IL-6) is a multifunctional cytokine that plays a central role in host defense due to its wide range of immune and hematopoietic activities and also its potential ability to induce the acute phase response. The high concentration of IL-6 has implication in the pathology of some diseases especially in DHF/DSS patients. This cytokine play a crucial role in the enhanced production of anti-platelet or anti-endothelial cell auto antibodies local or systemic, elevated levels of tPA, as well as a deficiency in coagulation, leading to plasma leakage and bleeding. We describe the pathogenic, characteristic and mechanism of IL-6 during DV infection.

Platelet auto-antibodies in septicaemic patients.

Thrombocytopenia associated with acute Septicaemia has been reported which may be due to Disseminated Intravasscular Coagulation (DIC), but has also been reported even without any evidence of it. An immunological cause has been suggested to explain this observation. The present study involved the investigation of 50 patients with clinical and bacteriological evidence of Septicaemia. By Direct Platelet Suspension Immunofluorescence Test (PSIFT) antiplatelet antibodies were detected in 54% patients with septicaemia and 67.5% with those having thrombocytopenia. The septicaemic patients were treated with antibiotics (mean 14 days). After successful treatment, i.e., when there was no bacteriological evidence of septicaemia, there was in increase in the platelet count (> 150 x 10(9)/L) with a corresponding fall in "PSIFT" positivity in 17 cases (P < 0.001). Hence an immunological process is considered to play a significant role in the pathogenesis of thrombocytopenia in these patients with septicaemia.

Trombocitopenia isoinmune en un lactante / Isoimmune thrombocytopaenia in an infant

Se informa de un lactante menor, cuya madre padecía lupus eritematoso diseminado, el cual presentó trombocitopenia isoinmune. Se hace referencia al cuadro clínico y los estudios realizados para su identificación, y se comentan los principales aspectos terapéuticos y de protección al paciente

La inmunoperoxidasa en el estudio de las trombocitopenias inmunológicas / Immunoperoxidase in the studies of immune thrombocytopenias

The usefulness of different techniques to measure platelet bound IgG has been reviewed by George(16). We present here the results obtained with a technique designed to measure membrane bound IgG employing an anti-human IgG labeled with peroxidase and using O-dianisidine-H2O2 to reveal the enzymatic activity(17). We studied 152 patients with chronic autoimmune thrombocytopenic (ATP) including 120 adults and 32 children (age below 15 years old), diagnosed by exclusion of diseases that may be associated with thrombocytopenic purpura of either immune or non-immune mechanisms. Besides, 79 patients with thrombocytopenia related to other diseases were also evaluated. The normal values in 215 controls were 188 +/- 4 IgG molec/platelet (mean +/- SE), while in the whole population of chronic ATP the results were 4714 +/- 344, p < 0.001. In pediatric cases the results had a tendency to values higher than in adults. A negative correlation was found between the number of platelets and the amount of bound IgG, r = 0.41 p < 0.001. IgG bound platelets were also increased in treated patients at relapse. The percent of normal IgG bound platelet was 4,5 percent in patients with a platelet count below 50.000/microliter and 39 percent in those with normal platelet number. Patients with secondary thrombocytopenia had elevated IgG/platelet while the values were normal in patients with thrombocytopenia of unknown etiology. We conclude that the immunoperoxidase technique is useful to establish the immunologic nature of thrombocytopenia.

Anticardiolipin antibodies, hemolytic anemia and thrombocytopenia in systemic lupus erythematosus

29 patients with SLE [27 females and 2 males], mean age [26.5 years]. 11 of these patients had autoimmune hemolytic anemia [AIHA] and 18 SLE patients without AIHA [control patients]. Anticardiolipin [ACL] antibodies IgG and IgM levels were measured by ELISA. Elevated IgM ACL antibodies were seen in 7 [63.6%] of 11 patients with AIHA and 2 [11.1%] of 18 control SLE patients [P <0.01]. There was no significant difference in IgG ACL antibodies levels between the two groups. Thrombocytopenia was present in 7 [63.6%] of 11 patients with AIHA and 4 [22.2%] of 18 control SLE patients [P <0.05]. Elevated IgG ACL antibodies were found in 3 [75%] of 4 control SLE patients with thrombocytopenia, [P <0.05] while IgM ACL antibodies were not detected in these patients. It was concluded that in patients with SLE and autoimmune hemolytic anemia, there is a high prevalence of both thrombocytopenia and IgM ACL antibodies which may act as anti- erythrocyte autoantibodies. Also, there is an association between IgG ACL antibodies and presence of thrombocytopenia in SLE. These antibodies may play a direct role in mediating platelet destruction

Dois casos de vasculite cutânea grave com plaquetopenia associada à cirrose hepática: componente autoimune e infecto-inflamatório com lesäo endotelial e padräo restritivo pulmonar em um caso / Two cases of severe cutaneous vasculitis with thrombocytopenia associated with hepatic cirrhosis: autoimmune and infect-inflammatory component with endotelial lesion and restrictive pulmonary pattern in one case

Descritos dois casos clínicos de pacientes do sexo feminino com cirrose hepática criptogênica em um e pelo vírus C em outro, com envolvimento autoimune multissistêmicos e intercorrência infecciosa. O caso 1 apresentou endocardite infecciosa e erisipela em membro inferior esquerdo. Em sua evoluçäo clínica ocorreu vasculite cutânea em membro inferior, plaquetopenia autoimune, leucopenia e quadro retritivo pulmonar com padräo inflamatótio. Havia imunecomplexos elevados e consumo de complemento. O caso 2 apresentou erisipela em membro inferior seguido por vasculite cutânea no local e consumo de complemento. O Caso 1 recebeu antibioticoterapia por 4 semanas para endocardite infecciosa, seguido por corticoterapia (prednisona) na dose de 1mg/Kg, com revisäo da plaquetopenia e leucopenia. O caso 2 apresentou melhora apenas com antibióticos. A relaçäo entre hepatopatias crônicas e fenômenos autoimunes sistemicos é discutida com ênfase para o comprometimento cutâneo, hematológico e pulmonar

Sindrome antifosfolipide e gestacao / Antiphospholipid syndrome and pregnancy

Os autores conceituam a sindrome antifosfolipide abordando aspectos sobre seu diagnostico bem como sua relacao com historia de perdas fetais de repeticao, particularmente no segundo e terceiro trimestre de gravidez. Analisam os possiveis tratamentos e as perspectivas futuras das gestantes portadoras de anticorpos antifosfolipides.