Trombastenia de Glanzmann: conceptos clave de la enfermedad / Glanzmann thrombasthenia: key concepts of the disease

La trombastenia de Glanzmann (TG), es un trastorno autosómico recesivo en el cual hay una reducción grave o ausencia de la agregación plaquetaria. Se debe a las alteraciones cualitativas o cuantitativas de la integrina α IIb o de integrina β 3, codificados por los genes ITGA2B e ITGB3 y relacionadas con la glicoproteína IIb/IIIa, que intervienen en la activación plaquetaria. La mayor incidencia de TG ha sido reportada en la población judía-iraquí, pero también se ha presentado en Israel, Jordania, Arabia saudita, Italia y, en menor número, en familias gitanas y pakistaníes. A pesar de ser poco frecuente, este trastorno se debe sospechar en casos de trastornos hemorrágicos graves espontáneos o inducidos por traumatismos, que varían desde hemorragias gastrointestinales y mucocutáneas, como epistaxis y hemorragias gingivales recurrentes de difícil manejo, las cuales son potencialmente mortales y en más del 75 por ciento de los casos requieren transfusión sanguínea o plaquetaria. Para realizar la confirmación del diagnóstico, los hallazgos de laboratorio se caracterizan por tiempos de sangrado prolongados, retracción del coágulo disminuida y respuestas anormales de agregación plaquetaria a estímulos fisiológicos. Aunque, actualmente no existe una cura para la enfermedad, el tratamiento adecuado con transfusiones plaquetarias y en caso de refractariedad, el uso del factor VIIa, permiten un buen pronóstico para los pacientes. Aún queda mucho por estudiar en estos casos debido a esto se están realizando nuevos estudios para la posibilidad de otros tratamientos, entre ellos la terapia génica plaquetaria(AU)

Glanzmann's thrombasthenia (GT) is an autosomal recessive disorder in which there is a severe reduction or absence of platelet aggregation. It is due to the qualitative or quantitative alterations of integrin #945; IIb or integrin #946; 3, encoded by the ITGA2B and ITGB3 genes and related to glycoprotein IIb / IIIa, which intervene in platelet activation. The highest incidence of GT has been reported in the Jewish-Iraqi population, but it has also been reported in Israel, Jordan, Saudi Arabia, Italy, and in smaller numbers in Gypsy and Pakistani families. Despite being uncommon, this disorder should be suspected in cases of severe spontaneous or trauma-induced bleeding disorders, ranging from gastrointestinal and mucocutaneous hemorrhages such as epistaxis and recurrent, difficult to manage gingival hemorrhages, which are potentially fatal and more than 75 percent of cases require blood or platelet transfusion. To confirm the diagnosis, the laboratory findings are characterized by prolonged bleeding times, decreased clot retraction and abnormal platelet aggregation responses to physiological stimuli. Although there is currently no cure for the disease, adequate treatments with platelet transfusions and in case of refractoriness, the use of factor VIIa, allow a good prognosis for patients. There is still much to study in these cases, because of this, new studies are being conducted for the possibility of other treatments, including platelet gene therapy(AU)

In-Lab Upfront Use of Tirofiban May Reduce the Occurrence of No-Reflow During Primary Percutaneous Coronary Intervention. A Pilot Randomized Study / Uso de Tirofibana em Laboratório pode Reduzir Ocorrência de não Reperfusão Durante Intervenção Coronariana Percutânea Primária. Um Estudo Piloto Randomizado

Abstract Background: Despite successful opening of culprit coronary artery, myocardial reperfusion does not always follows primary percutaneous coronary intervention (PPCI). Glycoprotein IIb/IIIa inhibitors are used in the treatment of no-reflow (NR), but their role to prevent it is unproven. Objective: To evaluate the effect of in-lab administration of tirofiban on the incidence of NR in ST-elevation myocardial infarction (STEMI) treated with PPCI. Methods: STEMI patients treated with PPCI were randomized (24 tirofiban and 34 placebo) in this double-blinded study to assess the impact of intravenous tirofiban on the incidence of NR after PPCI according to angiographic and electrocardiographic methods. End-points of the study were: TIMI-epicardial flow grade; myocardial blush grade (MBG); resolution of ST-elevation < 70% (RST < 70%) at 90min and 24h after PPCI. Results: Baseline anthropometric, clinical and angiographic characteristics were balanced between the groups. The occurrence of TIMI flow < 3 was not significantly different between the tirofiban (25%) and placebo (35.3%) groups. MBG ≤ 2 did not occur in the tirofiban group, and was seen in 11.7% of patients in the placebo group (p=0.13). RST < 70% occurred in 41.6% x 55.8% (p=0.42) at 90min and in 29% x 55.9% (p=0.06) at 24h in tirofiban and placebo groups, respectively. Severe NR (RST ≤ 30%) was detected in 0% x 26.5% (p=0.01) at 90 min, and in 4.2% x 23.5% (p=0.06) at 24h in tirofiban and placebo groups, respectively. Conclusion: This pilot study showed a trend toward reduction of NR associated with in-lab upfront use of tirofiban in STEMI patients treated with PPCI and paves the way for a full-scale study testing this hypothesis.

Resumo Fundamento: Mesmo com abertura da artéria coronária culpada bem sucedida, a reperfusão miocárdica nem sempre sucede a intervenção coronariana percutânea primária (ICPP). Inibidores da glicoproteína IIb/IIIa são usados no tratamento do fenômeno de não reperfusão (NR), mas seu papel para preveni-lo não está comprovado. Objetivo: Avaliar o efeito da administração, em laboratório, de tirofibana sobre a incidência de NR em infarto agudo do miocárdio com supra do segmento ST (IAMCSST) tratado com ICPP. Métodos: Pacientes com IAMCSST tratados com ICPP foram randomizados (24 tirofibana e 34 placebo) neste estudo duplo-cego para avaliar o impacto de tirofibana intravenosa sobre a incidência de NR após ICPP de acordo com métodos angiográficos e eletrocardiográfico. Os desfechos do estudo foram: fluxo epicárdico TIMI (grau), grau de fluxo miocárdico (MBG), resolução da elevação do segmento ST < 70% (RST < 70%) aos 90 minutos e 24 horas após ICPP. Resultados: Características antropométricas, clínicas e angiográficas basais eram equilibradas entre os grupos. A ocorrência de fluxo TIMI < 3 não foi significativamente diferente entre os grupos tirofibana (25%) e placebo (35,3%). MBG ≤ 2 não ocorreu no grupo tirofibana, e foi detectado em 11,7% dos pacientes do grupo placebo (p=0,13). RST < 70% ocorreu em 41,6% x 55,8% (p=0.42) aos 90 minutos, e em 29% x 55,9% (p=0,06) em 24 horas nos grupos tirofibana e placebo, respectivamente. NR grave (RST ≤ 30%) ocorreu em 0% x 26,5% (p=0,01) aos 90 minutos, e em 4,2% x 23,5% (p=0,06) em 24 horas nos grupos tirofibana e placebo, respectivamente. Conclusão: Este estudo piloto mostrou uma tendência de redução de NR associada ao uso, em laboratório, de tirofibana em pacientes com IAMCSST tratados com ICPP, e abre caminho para um estudo em escala real que teste essa hipótese.

Gene mutations of platelet glycoproteins and response to tirofiban in acute coronary syndrome / Mutações gênicas das glicoproteínas plaquetárias e resposta ao tirofiban na síndrome coronariana aguda

CONTEXT AND OBJECTIVES: Glycoprotein inhibitors (abciximab, eptifibatide and tirofiban) are used in patients with unstable angina and non-ST-segment elevation myocardial infarction before percutaneous coronary intervention. Of these, tirofiban is the least effective. We hypothesized that the response to tirofiban might be associated with glycoprotein gene mutations. DESIGN AND SETTING: Prospective study at Emergency Unit, Heart Institute (InCor), University of São Paulo. METHOD: Intrahospital evolution and platelet aggregation in response to tirofiban were analyzed in relation to four glycoprotein mutations in 50 patients indicated for percutaneous coronary intervention: 17 (34%) with unstable angina and 33 (66%) with non-ST-segment elevation myocardial infarction. Platelet aggregation was analyzed using the Born method. Blood samples were obtained before and one hour after tirofiban infusion. Glycoproteins Ia (807C/T ), Ib (Thr/Met) , IIb (Ile/Ser ) and IIIa (PIA ) were the mutations selected. RESULTS: Hypertension, dyslipidemia, diabetes, smoking, previous coronary artery disease and stroke were similar between the groups. Mutant glycoprotein IIIa genotypes had lower platelet aggregation before tirofiban administration than that of the wild genotype (41.0% ± 22.1% versus 55.9% ± 20.8%; P = 0.035). Mutant glycoprotein IIIa genotypes correlated moderately with lower platelet inhibition (r = -0.31; P = 0.030). After tirofiban administration, platelet glycoprotein Ia, Ib, IIb and IIIa mutations did not influence the degree of inhibition of platelet aggregation or intrahospital mortality. CONCLUSIONS: Mutations of glycoproteins Ia, Ib, IIb and IIIa did not influence platelet aggregation in response to tirofiban in patients with unstable angina and non-ST-segment elevation myocardial infarction.

RESUMO CONTEXTO E OBJETIVOS: Inibidores da glicoproteína (abciximab, eptifibatide, tirofiban) são utilizados em pacientes com angina instável e infarto do miocárdio sem elevação do segmento ST (IAMSSST) antes da intervenção coronária percutânea. Dentre eles, o tirofiban é o menos eficaz. Nossa hipótese é que a resposta ao tirofiban possa estar associada a mutações no gene da glicoproteína. DESENHO E LOCAL: Estudo prospectivo na Unidade de Emergência do Instituto do Coração (InCor), Universidade de São Paulo (USP). MÉTODOS: Foram analisadas a evolução intra-hospitalar e agregabilidade plaquetária em resposta ao tirofiban de 4 mutações da glicoproteína em 50 pacientes com indicação para intervenção coronária percutânea, 17 (34%) com angina instável e 33 (66%) com IAMSSST. A agregação plaquetária foi analisada pelo método de Born. Amostras de sangue foram obtidas antes e uma hora após infusão do tirofiban. As glicoproteínas Ia (807C/T ), Ib (Thr/Met ), IIb (Ile/Ser ) e IIIa (PIA ) foram as mutações selecionadas. RESULTADOS: Hipertensão, dislipidemia, diabetes, tabagismo, doença coronariana e acidente vascular cerebral prévios foram semelhantes entre os grupos. Observou-se menor agregabilidade plaquetária dos genótipos mutantes da glicoproteína IIIa antes da administração de tirofiban do genótipo selvagem (41% ± 22% versus 56% ± 21%; P = 0,035). Genótipos mutantes da glicoproteína IIIa correlacionaram-se moderadamente com menor inibição plaquetária (r = -0,31; P = 0,030). Após a administração tirofiban, as mutações das glicoproteínas Ia, Ib, IIb, e IIIa não influenciaram o grau de inibição da agregação plaquetária e mortalidade intra-hospitalar. CONCLUSÕES: Mutações das glicoproteínas Ia, Ib, IIb e IIIa não influenciaram a agregação plaquetária em resposta ao tirofiban nos pacientes com angina instável e IAMSSST.

Research progress of application of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syn-drome / 心血管康复医学杂志

Through occupying binding site of glycoprotein IIb/IIIa receptor,platelet glycoprotein IIb/IIIa inhibitor (GPI)inhibit the combination of fibrinogen and the receptor,then inhibit platelet aggregation.GPI is the most powerful anti-platelet drug and possesses application value in ACS now.This article made an overview on the newest research progress of safety and effectiveness of GPI in ACS.

Inhibition of platelet aggregation and immunomodulation of NK lymphocytes by administration of ascorbic acid.

Platelets aggregation around migrating tumor cells offers protection against the cytotoxic activity of the natural killers cells (NKC). The ascorbic acid in 3X10-3Μ concentration completely inhibited platelet aggregation, decreased thromboxane B2 levels, and inhibited the expression of platelet membranic receptor GpIIb/IIIa in non stimulated platelets, and increased the NKC cytotoxicity in an average rate of 105, 61, and 285% in the NKC/targets cells ratios 12.5:1, 25:1 and 50:1 respectively. The results suggest the role of ascorbic acid in increasing the susceptibility of tumor cells to NKC; the ascorbic acid could be used as part of a multidrug therapy to treat diseases which up to now have been treated only through chemotherapy.