Nuevos anticoagulantes orales en fibrilación auricular / New oral anticoagulants in atrial fibrillation

La fibrilación auricular es la arritmia más frecuente y se relaciona con una alta tasa de accidente cerebrovascular y embolia sistéc)mica. La terapia establecida tanto para prevención primaria como secundaria es la anticoagulación con warfarina, antagonista de la vitamina K. Existen escalas que predicen el riesgo tromboembólico y la probabilidad de beneficiarse de terapia antitrombótica. El CHADS2ha sido la más simple y ampliamente utilizada, pero actualmente el CHA2DS2-VASc ha incorporado otros factores de riesgo, otorgando una mejor estratificación. El estrecho margen terapéc)utico de la warfarina y la interacción con fármacos y alimentos requiere controles seriados de la intensidad de la anticoagulación, limitando su uso clínico. Han aparecido nuevos anticoagulantes que ofrecen ventajas sobre los antagonistas de vitamina K. Estos actúan en dos sitios distintos de la cascada de la coagulación: inhibiendo directamente la trombina como el dabigatran, o el factor X activado como el rivaroxaban, apixaban, edoxaban y betrixaban. Estos nuevos fármacos han ido reemplazando a la warfarina y ya están incluidos en las guías de manejo de fibrilación auricular no valvular.

Atrial fibrillation is the most common arrhythmia and is a major risk factor for ischemic stroke and systemic embolism. The therapy for primary and secondary prevention is the anticoagulation with warfarin; antagonist of vitamin K. There are scores to predict the risk of thromboembolism and the benefit of the antitrombotic therapy. The CHADS2 score has been the easiest one and it has been used widely, but today the CHA2DS2-VASc score includes new risk factors and gives a better risk stratification. The narrow therapeutic. margin and the interaction with food and drugs requires frequents tests of intensity of anticoagulation limiting usefulness in clinical practice. There are new anticoagulants that offer advantages compared with warfarin. These drugs act in two different points of the cascade of anticoagulation; directly inhibiting thrombin like dabigatran or factor X activated like rivaroxaban, apixaban, edoxaban and betrixaban. These new agents are replacing warfarin and they are already included in the guidelines of atrial fibrillation.

Leishmania amazonensis exhibits phosphatidylserine-dependent procoagulant activity, a process that is counteracted by sandfly saliva

Leishmania parasites expose phosphatidylserine (PS) on their surface, a process that has been associated with regulation of host's immune responses. In this study we demonstrate that PS exposure by metacyclic promastigotes of Leishmania amazonensis favours blood coagulation. L. amazonensis accelerates in vitro coagulation of human plasma. In addition, L. amazonensis supports the assembly of the prothrombinase complex, thus promoting thrombin formation. This process was reversed by annexin V which blocks PS binding sites. During blood meal, Lutzomyia longipalpis sandfly inject saliva in the bite site, which has a series of pharmacologically active compounds that inhibit blood coagulation. Since saliva and parasites are co-injected in the host during natural transmission, we evaluated the anticoagulant properties of sandfly saliva in counteracting the procoagulant activity of L. amazonensis . Lu. longipalpis saliva reverses plasma clotting promoted by promastigotes. It also inhibits thrombin formation by the prothrombinase complex assembled either in phosphatidylcholine (PC)/PS vesicles or in L. amazonensis . Sandfly saliva inhibits factor X activation by the intrinsic tenase complex assembled on PC/PS vesicles and blocks factor Xa catalytic activity. Altogether our results show that metacyclic promastigotes of L. amazonensis are procoagulant due to PS exposure. Notably, this effect is efficiently counteracted by sandfly saliva.

Nuevos anticoagulantes orales / New oral anticoagulant drugs

Thromboembolic disease (TED) is the leading cause of morbidity and mortality worldwide. The hallmark of oral long-term anticoagulant therapy has been the use of vitamin K antagonists, whose anticoagulant effect is exerted inhibiting vitamin K epoxide reductase. Warfarin and acenocoumarol are the most commonly used. In the last five years several new drugs for long term anticoagulation have been developed, which can inhibit single clotting factors with the purpose of improving drug therapeutic range and, ideally, minimizing bleeding risks. This review addresses the state of the art on the clinical use of inhibitors of activated factor X and thrombin.

Heparin induced thrombocytopenia.

Heparin induced thrombocytopenia (HIT) is a serious and life endangering complication of heparin therapy. It usually occurs after 5-14 days of continuous heparin therapy. It is immune mediated. Heparin, in the affected individual binds with platelet factor 4 (PF-4) and forms a highly antigenic Heparin PF-4 complex which leads to the generation of specific IgG Heparin PF4 antibodies (also called HIT antibodies). HIT antibodies may activate the platelets via Fcy receptor causing the release of highly coagulable micro particles which promote thrombosis--both venous and arterial. However, all patients with HIT antibodies do not progress to HIT with thrombosis (HITT). HIT can present as asymptomatic thrombocytopenia. It can also present with alarming features of venous and/or arterial thromboembolism, for example, pulmonary embolism from deep vein thrombosis (DVT), limb gangrene warranting amputation, cerebrovascular attack (CVA) or myocardial infarction (MI). Rare manifestation of HIT includes necrotizing skin lesion, acute anaphylactoid reaction following IV heparin bolus and acute adrenal apoplexy due to massive adrenal vein thrombosis. The diagnosis is based upon the combination of unexplained thrombocytopenia, demonstration of HIT antibodies, clinical profile and outcome of the case following withdrawal of heparin and administration of non-heparin anticoagulant like Lepirudin, Argatroban or Danaparoid. The choice of alternative anticoagulant depends upon the availability, cost, monitoring facilities and administrative guidelines.

Avances en la prevención de eventos tromboembólicos en pacientes con fibrilación auricular / Update on the prevention of thromboembolic phenomena in atrial fibrillation

Atrial fibrillation is the most common sustained arrhythmia in clinical practice and is associated to thromboembolic complications. Anticoagulation with vitamin K antagonists is clearly useful to reduce the incidence of emboli, but associated with important limitations. Therefore, there is an active search for medications that are more effective and simpler to prescribe and manage. Synthetic pentasaccharides of heparin such as idraparinux for parenteral use, showed promising results. Direct inhibitors of thrombin were also useful for the prevention of thromboembolism. However, they were withdrawn from the market due to potentially fatal adverse reactions. Other area of investigation has been the effectiveness of the combination of antiplatelet agents such as aspirin and clopidrogel. Although this combination is attractive, results of clinical trials must be awaited to have an opinion about its real usefulness. Finally, ieft atrial appendage transcatheter occlusion (PLAATO) is an effective and reasonably safe method for patients with contraindications for anticoagulation or those that continue to embolize despite well prescribed anticoagulation. The long term results of this intervention must also be awaited.

Antiplatelet and antithrombotic therapy in non ST elevation acute coronary syndrome: a review of current literature

The most important pathological mechanism in non-ST elevation Acute Coronary Syndrome [ACS] is the formation of a platelet rich thrombus on an atherosclerotic plaque. The understanding of this mechanism has changed the management of ACS with time. Until recently, the combination of aspirin and unfractionated heparin constituted the main antithrombotic therapy in ACS with a 46% reduction in vascular events, as reported by the Antithrombotic Trialists Collaboration. However, even with this regimen the recurrences of ischemic events in patients with ACS remained high. Now with the advent of newer drugs i.e., adenosine diphosphate [ADP] receptor antagonists and glycoprotein IIb/IIIa [GP IIb/IIIa] inhibitors, the out come of patients with ACS have significantly improved. The CURE trial clearly demonstrated the benefits of the combination of aspirin and clopidogrel in reducing major cardiovascular events by 20%. GP IIb/IIIa inhibitors, block the final common pathway of platelet aggregation. Agents like eptifibatide and tirofiban in large studies have demonstrated to cause reduction in 30 days risk of death and myocardial infarction. The risk reduction was greatest in patients with a baseline-elevated troponin, dynamic ST changes, recurrent angina, diabetes and in patients undergoing percutaneous revascularization. In view of the current evidence, appropriate selection of the antiplatelet and antithrombotic agents is the key for reduction in death and major adverse cardiac events in patients with ACS

Treating heparin-induced thrombocytopenia. the unconventional way!

Heparin-induced thrombocytopenia HIT is a potentially devastating complication of heparin therapy. The severe form of HIT has been associated with both venous and arterial thrombosis manifested by myocardial infarction, cerebrovascular occlusion, skin necrosis or limb ischemia. Several agents are now available as alternatives to heparin in patients with suspected HIT, including the thrombin specific inhibitors lepirudin and argatroban as well as the low molecular weight heparinoid known as danaparoid. When lacking these agents, here we report the use of plasmapheresis to create an artificial state of anticoagulation; exchanging patient's plasma with albumin rather than fresh frozen plasma, to allow the safe introduction of warfarin

Cofactor II de la heparina (HCII), un inhibidor de trombina cuyo rol fisiologico no esta completamente esclarecido / Heparin cofactor II, a thrombin inhibitor with a still unclarified physiologic role

El Cofactor II de la Heparina (HCII) es una proteína perteneciente al sistema de coagulación que inhibe específicamente trombina, processo que es potenciado por acción de los glicosaminoglicanos dermatán sulfato y heparina. Hasta el momento las deficiencias congénitas de HCII encontradas en forma aislada no están asociadas con eventos trombóticos, sí desarollan eventos trombóticos cuando están asociadas a otros factores predisponentes. Se observó disminución en los niveles de HCII en hepatopatías, coagulación intravascular diseminada, en anemia drepanocítica, encontrándose niveles elevados en embarazo a término y por el uso de contraceptivos orales. En el laboratorio realizamos el dosaje del HCII en la población normal de la ciudad de Buenos Aires, en diversas patologías como sepsis, quemados , anticoagulados con dicumarínicos y con heparina, diabéticos, hiperhomocisteinemia, observándose valores disminuidos principalmente en sepsis y pacientes diabéticos. El HCII es una glicoproteína que participa en la inhibición de trombina pero cuyo rol fisiológico no está completamente esclarecido. Es probable que el HCII inhiba trombina en el espacio extravascular, y está relacionado con la regulación de procesos inflamatorios y de reparación tisular.

Cofactor II de la heparina, valores de referencia, consumo en presencia de distintos glicosamoniaglicanos / Cofactor II, reference values consumption in the presence of different glycosaminoglycans

El Cofactor II de la Heparina (HCII) es una glicoproteína plasmática que inhibe rápidamente Trombina, en presencia de Glicosaminoaglicanos (GAGS) como Dermatán Sulfato (DS), Dextrán Sulfato (DX) y altas concentraciones de heparina. El nivel de actividad de HCII está marcadamente disminuido en pacientes con daño hepático severo, coagulación intravascular diseminada y en complicaciones obstétricas, siendo normales en la mayoría de pacientes con trombosis venosa. En este trabajo, se determinaron los valores de referencia para la actividad y antigenicidad de HCII para la población normal de Buenos Aires (Argentina). Los valores obtenidos: 70-130 por ciento actividad y 75-11- por ciento antigenicidad. Se midió la actividad de HCII en suero, siendo ésta entre un 20 a 40 por ciento menor que la del plasma. Se estudió también el consumo (CON) de HCII cuando se dejó coagular in vitro, sangre de individuos normales, en ausencia y presencia de distintas concentraciones de DS, DX y Heparina. El CON de HCII aumenta significativamente (p < 10-4) en presencia de DS, este incremento es aún mayor en presencia de DX, mientras que Heparina en las concentraciones utilizadas no modifica significativamente el CON de HCII. De lo cual se puede concluir, que si bien el DX es el mejor potenciador in vitro, su acción fisiológica sería escasa porque presenta una síntesis muy localizada, mientras que el DS desempeñaría un importante rol fisiológico como potenciador de HCII a nivel extravascular, ya que se sintetiza en los fibroblastos de la capa media de los vasos