Introduction: Bivalirudin and heparin are the two most commonly used anticoagulants used during Percutaneous Coronary Intervention (PCI). The results of Randomized Controlled Trials (RCTs) comparing bivalirudin versus heparin monotherapy in the era of radial access are controversial, questioning the positive impact of bivalirudin on bleeding. The purpose of this systematic review is to summarize the results of RCTs comparing the efficacy and safety of bivalirudin versus heparin with or without Glycoprotein IIb/IIIa Inhibitors (GPI). Methods: This systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses PRISMA statements for reporting systematic reviews. We searched the National Library of Medicine PubMed, Clinicaltrial.gov and the Cochrane Central Register of Controlled Trials to include clinical studies comparing bivalirudin with heparin in patients undergoing PCI. Sixteen studies met inclusion criteria and were reviewed for the summary. Findings: Several RCTs and meta-analyses have demonstrated the superiority of bivalirudin over heparin plus routine GPI use in terms of preventing bleeding complications but at the expense of increased risk of ischemic complications such as stent thrombosis. The hypothesis of post-PCI bivalirudin infusion to mitigate the risk of acute stent thrombosis has been tested in various RCTs with conflicting results. In comparison, heparin offers the advantage of having a reversible agent, of lower cost and reduced incidence of ischemic complications. Conclusion: Bivalirudin demonstrates its superiority over heparin plus GPI with better clinical outcomes in terms of less bleeding complications, thus making it as anticoagulation of choice particularly in patients at high risk of bleeding. Further studies are warranted for head to head comparison of bivalirudin to heparin monotherapy to establish an optimal heparin dosing regimen and post-PCI bivalirudin infusion to affirm its beneficial effect in reducing acute stent thrombosis.

Hjärt-kärl sjukdom är den vanligaste dödsorsaken i västvärlden. Samtidigt som antalet patienter med hjärtinfarkt har minskat, har antalet patienter med instabil kranskärlsjukdom d.v.s. svår kärlkramp ökat påtagligt. Diagnosen är nu den vanligaste orsaken till vård på hjärtinfarktavdelningar i Sverige. Modern behandling av instabil kranskärlssjukdom består av en kombination av läkemedel för att minska blodproppsbildning och avlasta hjärtarbetet samt, i de flesta fall, s.k. ballongvidning eller operation av hjärtats kranskärl. Trots stora behandlingsframsteg är risken för hjärtinfarkt och död hög, såväl på kort som lång sikt. Det finns därför ett stort behov av ytterligare förbättrad behandling utan att samtidigt erhålla oacceptabelt hög risk för allvarliga biverkningar. För att erbjuda en effektiv behandling till patienter med hög risk och samtidigt undvika dyr och potentiellt riskfylld behandling till patienter med låg risk behövs också bättre instrument för tidig riskbedömning. Syftet med avhandlingen var att undersöka en stor grupp patienter med instabil kranskärlssjukdom avseende säkerhet och effektivitet av en behandlingskombination av två moderna blodproppshämmande läkemedel, dalteparin och abciximab (ca 1000 patienter). Syftet var också att studera hur denna behandling påverkar system för inflammation och koagulation (ca 400 patienter). Dessutom ville vi värdera hur blodnivåer av markörer för inflammation, hjärtmuskelskada och nedsatt hjärtfunktion kan förutsäga risken för framtida komplikationer (ca 7000 patienter). Tillägg av abciximab till dalteparin minskade inte risken för dödsfall eller hjärtinfarkt inom trettio dagar. Däremot ökade antalet blödningskomplikationer. Totala antalet blödningar var emellertid relativt lågt och behandlingen syntes vara lika säker som kombinationen av abciximab och det internationellt mycket använda blodproppshämmande medlet heparin. Trots den kraftfulla behandlingskombinationen skedde en samtidig aktivering av system för såväl inflammation som koagulation. Detta kan vara en orsak till den observerade avsaknaden av behandlingseffekt av abciximab. Att hindra denna aktivering skulle samtidigt kunna innebära möjligheter för nya behandlingsstrategier. Förhöjda nivåer av markörer för hjärtmuskelskada (troponin T), inflammation (CRP), nedsatt hjärtfunktion (proBNP) eller nedsatt njurfunktion (kreatininclearance) ökade risken för dödlig utgång både på kort och lång sikt, oberoende av andra riskfaktorer. En kombination av två av dessa markörer gav den högsta risken för dödlig utgång. Således dog endast 0.3 % av patienter med låga nivåer av proBNP och normal njurfunktion inom ett år, jämfört med 25.7 % av patienter med höga nivåer av proBNP och nedsatt njurfunktion. Förhöjda nivåer av troponin T eller nedsatt kreatininclearance (men inte av CRP eller proBNP) ökade dessutom risken för hjärtinfarkt. Resultaten i avhandlingsarbetet har givit kliniskt tillämpbar kunskap om hur kärlkrampspatienter med hög respektive låg risk kan selekteras tidigt efter inkomst till sjukhus och ny kunskap om behandlingseffekt av abciximab och dalteparin. Resultaten har redovisats på internationella kongresser och i högt rankade medicinska tidskrifter och har citerats i europeiska och amerikanska ”guidelines” för behandling av instabil kranskärlssjukdom. / Patients with unstable coronary artery disease (CAD) have an increased risk of subsequent myocardial infarction and death. This study evaluated the safety and efficacy of treatment with glycoprotein IIb/IIIa inhibition in addition to aspirin, low molecular-weight heparin and its influence on coagulation and inflammation. Also, early and differentiated risk assessment utilising markers of inflammation, myocardial damage and dysfunction were evaluated. The Global Utilisation of Strategies To open Occluded arteries- IV (GUSTO-IV) trial randomised 7800 patients with unstable CAD to 24 or 48 hours infusion of abciximab or placebo in addition to routine treatment with aspirin and unfactionated heparin or dalteparin. Baseline levels of creatinine, C-reactive protein (CRP), Troponin-T (TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were analysed. At selected sites, all patients received subcutaneous dalteparin (n=974), in stead of unfractionated heparin infusion (n=6826). In a sub-population of dalteparin treated patients (n=404), serial measurements of markers of inflammation , coagulation and fibrinolysis were also performed. Addition of abciximab to dalteparin as the primary treatment of unstable CAD was not associated with any significant reduction in cardiac events but a doubled risk of bleedings. The combination of abciximab and dalteparin seemed to be as safe as when used with unfractionated heparin. Despite full dose dalteparin and aspirin there was a simultaneous activation of the inflammation, coagulation and fibrinolysis systems without any influence of the abciximab treatment. Elevated levels of CRP, TnT, and NT-proBNP and reduced creatinine clearance were independently related to short and long-term mortality. The best prediction of high and low risk was provided by a combination of NT-proBNP and creatinine clearance. Any detectable elevation of TnT and reduced creatinine clearance, but neither elevation of CRP nor NT-proBNP, were also independently associated to a raised risk of subsequent myocardial infarction.

Que o envenenamento pela serpente Bothrops jararaca causa distúrbios hemorrágicos sistêmicos, com alteração da coagulação e fibrinólise sangüíneas, é notório. Contudo, pouco se sabe sobre a ação in vivo desse veneno sobre as plaquetas. Em estudos recentes, demonstrou-se que esse veneno causa trombocitopenia, distúrbios da agregação e diminuição do número de corpos densos plaquetários, que, dessarte, sugeriam a ativação das plaquetas circulantes. Com o escopo de comprovar esta hipótese e melhor caracterizar as ações in vivo desse veneno sobre as plaquetas, serviu-se de um modelo experimental que empregava coelhos para o envenenamento pela B. jararaca. No grupo experimental, os animais foram injetados i.v. com o veneno da B. jararaca (60 µg/kg) e no grupo controle com salina. Previamente à administração de salina ou veneno, os coelhos tiveram suas plaquetas marcadas ex vivo com NHS-biotina. Para a avaliação das alterações plaquetárias, amostras de sangue foram coletadas seqüencialmente, em intervalos de tempo que variaram de 1 a 144 horas após a administração do veneno ou salina. Durante o envenenamento, houve trombocitopenia, hipofibrinogenemia, elevação dos níveis plasmáticos do fator de von Willebrand, diminuição da função plaquetária no sangue total induzida pela botrocetina e pelo colágeno e diminuição da secreção de ATP. Não obstante, os níveis plasmáticos de fator plaquetário 4, um marcador específico da ativação plaquetária in vivo, e os níveis intraplaquetários de serotonina se mantiveram constantes. Pela citometria de fluxo, observou-se um decréscimo significativo da expressão do epítopo da GPIIb-IIIa reconhecido pelo anticorpo monoclonal P2, porém isso não foi observado ao utilizar-se anticorpos policlonais. A expressão de fibrinogênio ou dos produtos de degradação do fibrinogênio/fibrina (PDF) na membrana plaquetária também não sofreu alteração significativa ao longo do tempo. Houve, todavia, elevações significativas da P-selectina plaquetária, um receptor cuja expressão é indicativa de ativação plaquetária, e do epítopo induzido por ligantes (LIBS1) da GPIIIa. A porcentagem de plaquetas reticuladas na circulação, assim como os tempos de sobrevivência plaquetária, não foram estatisticamente diferentes entre os dois grupos. As análises histológicas e imuno-histoquímicas dos órgãos dos coelhos mostraram que as plaquetas circulantes são retidas entre redes de fibrina nos capilares pulmonares. Os resultados obtidos sugerem que a trombina engendrada pelos componentes pró-coagulantes deste veneno desempenha uma função essencial na patogenia dos distúrbios da coagulação e plaquetários observados neste modelo de envenenamento. O aumento da expressão de P-selectina no grupo experimental comprovou a hipótese inicial de que as plaquetas dos coelhos envenenados são verdadeiramente ativadas na circulação. Os dados ora apresentados demonstram definitivamente que a diminuição do fibrinogênio ou o aumento dos PDF não são a causa fundamental da disfunção plaquetária observada no envenenamento botrópico e que outro(s) composto(s) parece(m) estar envolvido(s) com estes distúrbios plaquetários. / In spite of being well established that Bothrops jararaca snake venom causes blood coagulation and fibrinolysis disturbances in patients, scant information about blood platelet disorders during envenomation is available. In recent investigations, thrombocytopenia, platelet aggregation disturbances and decreased numbers of platelet dense bodies were observed following venom administration, suggesting that circulating platelets had been activated. In order to prove this hypothesis and to gain a better characterization of the in vivo role of this venom on platelets, an experimental model of B. jararaca envenomation was utilized. Rabbits were injected i.v. either with B. jararaca venom (60 µg/kg) (experimental group) or saline (control group). Previously to saline or venom administration, rabbit platelets were labeled ex vivo with NHS-biotin. To evaluate platelet disturbances, blood samples were collected consecutively, at time intervals that varied from 1 to 144 hours after venom or saline administration. During envenomation, there were thrombocytopenia, hypofibrinogenemia, elevation of von Willebrand factor plasma levels, reduced botrocetin- and collagen-induced platelet aggregation in whole blood, and decreased ATP secretion. However, plasma levels of platelet factor 4, a specific marker of in vivo platelet activation, and intraplatelet serotonin levels remained constant. By flow cytometry, a significant decrease on the expression of GPIIb-IIIa epitope recognized by P2 monoclonal antibody was observed; however, this was not observed when polyclonal antibodies were employed. Fibrinogen or fibrin(ogen) degradation product (FDP) expression on platelet surface showed no significant alteration. Nonetheless, significant elevations of platelet P-selectin, a receptor whose expression is indicative of platelet activation, and of ligand-induced binding sites (LIBS1) of GPIIIa were noted. The percentage of circulating reticulated platelets, as well as platelet survival times, were not statistically different between the two groups. Histopathological and immunohistochemical analyses of rabbit organs demonstrated that circulating platelets were sequestered among fibrin deposits in pulmonary capillaries. These results suggest that thrombin generated by procoagulating components of B. jararaca venom has an essential role in the pathogenesis of platelet and coagulation disorders in this experimental model. Increased expression of P-selectin in the experimental group proves the initial hypothesis that platelets of envenomed rabbits are indeed activated in the circulation. The data presented herein demonstrate definitively that decreased fibrinogen or increased FDP levels are not the primary cause of the platelet dysfunction observed in bothropic envenomation, but other substances seem to be responsible for it.

Que o envenenamento pela serpente Bothrops jararaca causa distúrbios hemorrágicos sistêmicos, com alteração da coagulação e fibrinólise sangüíneas, é notório. Contudo, pouco se sabe sobre a ação in vivo desse veneno sobre as plaquetas. Em estudos recentes, demonstrou-se que esse veneno causa trombocitopenia, distúrbios da agregação e diminuição do número de corpos densos plaquetários, que, dessarte, sugeriam a ativação das plaquetas circulantes. Com o escopo de comprovar esta hipótese e melhor caracterizar as ações in vivo desse veneno sobre as plaquetas, serviu-se de um modelo experimental que empregava coelhos para o envenenamento pela B. jararaca. No grupo experimental, os animais foram injetados i.v. com o veneno da B. jararaca (60 µg/kg) e no grupo controle com salina. Previamente à administração de salina ou veneno, os coelhos tiveram suas plaquetas marcadas ex vivo com NHS-biotina. Para a avaliação das alterações plaquetárias, amostras de sangue foram coletadas seqüencialmente, em intervalos de tempo que variaram de 1 a 144 horas após a administração do veneno ou salina. Durante o envenenamento, houve trombocitopenia, hipofibrinogenemia, elevação dos níveis plasmáticos do fator de von Willebrand, diminuição da função plaquetária no sangue total induzida pela botrocetina e pelo colágeno e diminuição da secreção de ATP. Não obstante, os níveis plasmáticos de fator plaquetário 4, um marcador específico da ativação plaquetária in vivo, e os níveis intraplaquetários de serotonina se mantiveram constantes. Pela citometria de fluxo, observou-se um decréscimo significativo da expressão do epítopo da GPIIb-IIIa reconhecido pelo anticorpo monoclonal P2, porém isso não foi observado ao utilizar-se anticorpos policlonais. A expressão de fibrinogênio ou dos produtos de degradação do fibrinogênio/fibrina (PDF) na membrana plaquetária também não sofreu alteração significativa ao longo do tempo. Houve, todavia, elevações significativas da P-selectina plaquetária, um receptor cuja expressão é indicativa de ativação plaquetária, e do epítopo induzido por ligantes (LIBS1) da GPIIIa. A porcentagem de plaquetas reticuladas na circulação, assim como os tempos de sobrevivência plaquetária, não foram estatisticamente diferentes entre os dois grupos. As análises histológicas e imuno-histoquímicas dos órgãos dos coelhos mostraram que as plaquetas circulantes são retidas entre redes de fibrina nos capilares pulmonares. Os resultados obtidos sugerem que a trombina engendrada pelos componentes pró-coagulantes deste veneno desempenha uma função essencial na patogenia dos distúrbios da coagulação e plaquetários observados neste modelo de envenenamento. O aumento da expressão de P-selectina no grupo experimental comprovou a hipótese inicial de que as plaquetas dos coelhos envenenados são verdadeiramente ativadas na circulação. Os dados ora apresentados demonstram definitivamente que a diminuição do fibrinogênio ou o aumento dos PDF não são a causa fundamental da disfunção plaquetária observada no envenenamento botrópico e que outro(s) composto(s) parece(m) estar envolvido(s) com estes distúrbios plaquetários. / In spite of being well established that Bothrops jararaca snake venom causes blood coagulation and fibrinolysis disturbances in patients, scant information about blood platelet disorders during envenomation is available. In recent investigations, thrombocytopenia, platelet aggregation disturbances and decreased numbers of platelet dense bodies were observed following venom administration, suggesting that circulating platelets had been activated. In order to prove this hypothesis and to gain a better characterization of the in vivo role of this venom on platelets, an experimental model of B. jararaca envenomation was utilized. Rabbits were injected i.v. either with B. jararaca venom (60 µg/kg) (experimental group) or saline (control group). Previously to saline or venom administration, rabbit platelets were labeled ex vivo with NHS-biotin. To evaluate platelet disturbances, blood samples were collected consecutively, at time intervals that varied from 1 to 144 hours after venom or saline administration. During envenomation, there were thrombocytopenia, hypofibrinogenemia, elevation of von Willebrand factor plasma levels, reduced botrocetin- and collagen-induced platelet aggregation in whole blood, and decreased ATP secretion. However, plasma levels of platelet factor 4, a specific marker of in vivo platelet activation, and intraplatelet serotonin levels remained constant. By flow cytometry, a significant decrease on the expression of GPIIb-IIIa epitope recognized by P2 monoclonal antibody was observed; however, this was not observed when polyclonal antibodies were employed. Fibrinogen or fibrin(ogen) degradation product (FDP) expression on platelet surface showed no significant alteration. Nonetheless, significant elevations of platelet P-selectin, a receptor whose expression is indicative of platelet activation, and of ligand-induced binding sites (LIBS1) of GPIIIa were noted. The percentage of circulating reticulated platelets, as well as platelet survival times, were not statistically different between the two groups. Histopathological and immunohistochemical analyses of rabbit organs demonstrated that circulating platelets were sequestered among fibrin deposits in pulmonary capillaries. These results suggest that thrombin generated by procoagulating components of B. jararaca venom has an essential role in the pathogenesis of platelet and coagulation disorders in this experimental model. Increased expression of P-selectin in the experimental group proves the initial hypothesis that platelets of envenomed rabbits are indeed activated in the circulation. The data presented herein demonstrate definitively that decreased fibrinogen or increased FDP levels are not the primary cause of the platelet dysfunction observed in bothropic envenomation, but other substances seem to be responsible for it.