Pharmacological Comparison of Human Internal Mammary Artery and Radial Artery in Terms of Conduits for Revascularization

Internal mammary arteries (IMA) are routinely used for coronary artery bypass grafting (CABG), but can exhibit impairment of endothelium-dependent vascular relaxation. The use of radial artery (RA) grafts for CABG has been recently reintroduced. The long-term patency of these grafts may depend on the ability of these vessels to produce endotheliumderived nitric oxide (NO). We therefore sought to determine if the RA exhibits better endothelial function compared with IMA harvested from the same patient. Using the organ bath technique, vessels were preconstricted with the thromboxane A2 analogue (U46619) and exposed to increasing concentrations of either acetylcholine (ACh ), calcium ionophore A23187 (A23187), or nitroglycerin (NTG). We prepared the rubbed RA for comparison of between RA with and without endothelium on response to ACh relaxation. KCI and U46619 constricted RA (11.3ﾂｱ4.9g and 16.0ﾂｱ4.3g respectively) more than IMA(2.4ﾂｱ1.4g and 4.5ﾂｱ1.7 respectively). Both RA and IMA relaxed 100% of the preconstricted tension to NTG. ACh induced less relaxation in the IMA(28ﾂｱ24%) when compared with the RA(49ﾂｱ16%)(p<0.05). A23187 demonstrated relaxation in both the RA(86ﾂｱ14%)and IMA(76ﾂｱ18%), but there was no statistical difference. RA without endothelium showed same response to ACh as IMAs. Compared with the IMA, the RA has better ACh induced endothelium-dependent relaxation. This pathway mainly involves NO production which also inhibits the atherosclerotic process. Therefore, the RA may provide longer term graft patency than IMA

Differential Contributions of Intrinsic and Extrinsic Pathways to Thrombin Generation in Adult, Maternal and Cord Plasma Samples.

BACKGROUND:Thrombin generation (TG) is a pivotal process in achieving hemostasis. Coagulation profiles during pregnancy and early neonatal period are different from that of normal (non-pregnant) adults. In this ex vivo study, the differences in TG in maternal and cord plasma relative to normal adult plasma were studied. METHODS:Twenty consented pregnant women and ten consented healthy adults were included in the study. Maternal and cord blood samples were collected at the time of delivery. Platelet-poor plasma was isolated for the measurement of TG. In some samples, anti-FIXa aptamer, RB006, or a TFPI inhibitor, BAX499 were added to elucidate the contribution of intrinsic and extrinsic pathway to TG. Additionally, procoagulant and inhibitor levels were measured in maternal and cord plasma, and these values were used to mathematically simulate TG. RESULTS:Peak TG was increased in maternal plasma (393.6±57.9 nM) compared to adult and cord samples (323.2±38.9 nM and 209.9±29.5 nM, respectively). Inhibitory effects of RB006 on TG were less robust in maternal or cord plasma (52% vs. 12% respectively) than in adult plasma (81%). Likewise the effectiveness of BAX499 as represented by the increase in peak TG was much greater in adult (21%) than in maternal (10%) or cord plasma (12%). Further, BAX499 was more effective in reversing RB006 in adult plasma than in maternal or cord plasma. Ex vivo data were reproducible with the results of the mathematical simulation of TG. CONCLUSION:Normal parturient plasma shows a large intrinsic pathway reserve for TG compared to adult and cord plasma, while TG in cord plasma is sustained by extrinsic pathway, and low levels of TFPI and AT

Anti-factor IXa Aptamer reduces propagation of thrombin generation in plasma anticoagulated with warfarin

Warfarin is routinely used in the prevention and treatment of prothrombotic events. During initiation of warfarin therapy levels of factor (F) VII and protein C decrease rapidly but prothrombin, FIX and FX decline much slower. Therefore, propagation of thrombin generation (TG) remains unaffected much longer, increasing the risk of inadequate anticoagulation. Recently, a novel agent, anti-IXa aptamer, RB006, has been developed. Therefore, we have evaluated the in vitro effects of this agent in warfarin plasma

Haemodilution-induced profibrinolytic state is mitigated by fresh-frozen plasma: implications for early haemostatic intervention in massive haemorrhage

Fibrinolysis contributes to coagulopathy after major trauma and surgery. We hypothesized that progressive haemodilution is responsible, at least in part, for increased fibrinolytic tendency of blood clot

Computational simulation and comparison of prothrombin complex concentrate dosing schemes for warfarin reversal in cardiac surgery

Background: Prothrombin complex concentrate (PCC) is increasingly used for acute warfarin reversal. We hypothesized that computational modeling of thrombin generation (TG) could be used to optimize the timing and dose of PCC during hemodilution induced by cardiopulmonary bypass (CPB). Methods: Thrombin generation patterns were modeled in anticoagulated patients (n = 59) using a published computational model. Four dosing schemes were evaluated including single full dose (median, 41.2 IU/kg) of PCC before or after CPB, ½-dose before and after CPB, or 1/3-dose before CPB plus 2/3-dose after CPB. Hemodilution was modeled as 40 or 60 % dilution of factors from baseline. The lag time (s) of TG, and peak thrombin level (nM) were evaluated. Results: Prolonged lag time, and reduced peak TG were due to low vitamin K-dependent (VKD) factors, and pre-CPB PCC dose-dependently restored TG to near-normal or normal range. After 40 % dilution, TG parameters were similar among 4 regimens at the end of therapy. The recovery of VKD factors was less when PCC was given before CPB after 60 % dilution, but TG parameters were considered hemostatically effective (\u3e200 nM) with any regimen. Withholding the full dose of PCC until post-CPB resulted in severely depressed TG peak (median, 47 nM) after 60 % dilution, and some supra-normal TG peaks after treatment. Conclusions: Pre-CPB administration of full or divided doses of PCC prevents extremely low TG peak during surgery, and maintains hemostatic TG peaks in both 40 and 60 % hemodilution models. Although PCC’s hemostatic activity appears to be highest using the full dose after CPB, hypercoagulability may develop in some cases

Differential Contributions of Intrinsic and Extrinsic Pathways to Thrombin Generation in Adult, Maternal and Cord Plasma Samples

<div><p>Background</p><p>Thrombin generation (TG) is a pivotal process in achieving hemostasis. Coagulation profiles during pregnancy and early neonatal period are different from that of normal (non-pregnant) adults. In this <i>ex vivo</i> study, the differences in TG in maternal and cord plasma relative to normal adult plasma were studied.</p><p>Methods</p><p>Twenty consented pregnant women and ten consented healthy adults were included in the study. Maternal and cord blood samples were collected at the time of delivery. Platelet-poor plasma was isolated for the measurement of TG. In some samples, anti-FIXa aptamer, RB006, or a TFPI inhibitor, BAX499 were added to elucidate the contribution of intrinsic and extrinsic pathway to TG. Additionally, procoagulant and inhibitor levels were measured in maternal and cord plasma, and these values were used to mathematically simulate TG.</p><p>Results</p><p>Peak TG was increased in maternal plasma (393.6±57.9 nM) compared to adult and cord samples (323.2±38.9 nM and 209.9±29.5 nM, respectively). Inhibitory effects of RB006 on TG were less robust in maternal or cord plasma (52% <i>vs</i>. 12% respectively) than in adult plasma (81%). Likewise the effectiveness of BAX499 as represented by the increase in peak TG was much greater in adult (21%) than in maternal (10%) or cord plasma (12%). Further, BAX499 was more effective in reversing RB006 in adult plasma than in maternal or cord plasma. <i>Ex vivo</i> data were reproducible with the results of the mathematical simulation of TG.</p><p>Conclusion</p><p>Normal parturient plasma shows a large intrinsic pathway reserve for TG compared to adult and cord plasma, while TG in cord plasma is sustained by extrinsic pathway, and low levels of TFPI and AT.</p></div

In vitro effects of recombinant activated factor VII on thrombin generation and coagulation following inhibition of platelet procoagulant activity by prasugrel

Introduction Prasugrel is a thienopyridyl P2Y12 antagonist with potent antiplatelet effects. At present, little is known about its effects on thrombin generation or what strategies may emergently reverse its anticoagulant effects. In the current study we evaluated whether recombinant activated factor VII may reverse prasugrel induced effects and increase thrombin generation in an in vitro model. Methods The effect of prasugrel active metabolite, PAM (R-138727), was evaluated on platelet aggregation, thrombin generation, and rotational thromboelastometry parameters using blood from 20 healthy volunteers. Additionally, we evaluated the effects of adenosine diphosphate (ADP) and recombinant activated factor VII on restoring these parameters towards baseline values. Results PAM reduced maximum platelet aggregation and led to platelet disaggregation. It also decreased peak thrombin, increased lag time, and increased time to peak thrombin. Treatment with recombinant activated factor VII restored all three parameters of thrombin generation towards baseline. ADP decreased lag time and time to peak thrombin, but had no effect on peak thrombin. When recombinant activated factor VII and ADP were combined they had a greater effect on thrombin parameters than either drug alone. PAM also increased thromboelastometric clotting time and clot formation time, but had no effect on maximum clot firmness. Treatment with either recombinant activated factor VII or ADP restored these values towards baseline. Conclusions Recombinant activated factor VII restores thrombin generation in the presence of PAM. In patients taking prasugrel with life-threatening refractory bleeding it has the potential to be a useful therapeutic approach. Additional clinical studies are needed to validate our findings. © 2013 Elsevier Ltd. All rights reserved