Key Points Contribution of FXIa and platelet-derived polyphosphate in thrombin generation varies depending on surface tissue-factor level. Platelet-derived polyphosphate potentiates pathways downstream of FXIIa that require low participation of extrinsic pathways.
Many metal oxides and halides derive their conducting and magnetic properties from rapid self-exchange between metals in mixed oxidation states or from delocalized fractional valence states."] Hence, hybrid molecular systems derived from conjugated organic polymers which incorporate redox-active transition metal centers represent a promising approach to materials which display similar properties.Although there have been extensive investigations of polymers with redox-active metal there have been few examples of materials in which the metal-free organic portion is delocalized and electronically conductive.[41 The notion that a conductive polymer should be an efficient conduit for the electron transport makes intuitive sense. However, there is much to learn about how the degree of electronic communication between the redox centers and the polymer can influence the conductive and electrochemical properties of such materials. This understanding is certain to be useful for the development of materials for electr~catalytic,[~] sensory, and magnetic applications. Toward this end, we report herein the synthesis of a conducting p~lythiophene-Ru'@(bipy)~ hybrid material as well as the polymers derived from the non-metallated ligand. We find that this hybrid system exhibits high redox conductivity involving self-exchange between localized Run@ sites and thereby c o n h s the merits of this approach.Our choice of R~'@(bipy)~ centers as the redox component is the result of the broad manifold of reversible electrochemical activity displayed by this type of complex.[61 To achieve a maximum interaction between the polymer and the metal, the bipyridine ligands are incorporated directly into the polymer backbone. The thiophene residues were chosen to allow the polymer synthesis by electrochemical ~x i d a t i o n .~~] The first ligand investigated was 5,5'-bis(2"thiophene)-2,2'-bipyridine,
Generation of active Factor XII (FXIIa) triggers blood clotting on artificial surfaces and may also enhance intravascular thrombosis. We developed a patterned kaolin (0 to 0.3 pg/μm2)/type 1 collagen fibril surface for controlled microfluidic clotting assays. Perfusion of whole blood (treated only with a low level of 4 μg/mL of the XIIa inhibitor, corn trypsin inhibitor) drove platelet deposition followed by fibrin formation. At venous wall shear rate (100 s−1), kaolin accelerated onset of fibrin formation by ~100 sec when compared to collagen alone (250 sec vs. 350 sec), with little effect on platelet deposition. Even with kaolin present, arterial wall shear rate (1000 s−1) delayed and suppressed fibrin formation compared to venous wall shear rate. A comparison of surfaces for extrinsic activation (tissue factor TF/collagen) versus contact activation (kaolin/collagen) that each generated equal platelet deposition at 100 s−1 revealed: (1) TF surfaces promoted much faster fibrin onset (at 100 sec) and more endpoint fibrin at 600 sec at either 100 s−1 or 1000 s−1, and (2) kaolin and TF surfaces had a similar sensitivity for reduced fibrin deposition at 1000 s−1 (compared to fibrin formed at 100 s−1) despite differing coagulation triggers. Anti-platelet drugs inhibiting P2Y1, P2Y12, cyclooxygenase-1 or activating IP-receptor or guanylate cyclase reduced platelet and fibrin deposition on kaolin/collagen. Since FXIIa or FXIa inhibition may offer safe antithrombotic therapy, especially for biomaterial thrombosis, these defined collagen/kaolin surfaces may prove useful in drug screening tests or in clinical diagnostic assays of blood under flow conditions.
We assessed the phototoxicity of a series of xanthene derivatives against E. coli, S. aureus, and S. cerevisiae, measured the physicochemical properties of the photosensitizers, and found the relationship between them. Without illumination, the dyes tested showed almost the same level of inherent toxicity to the same organism, which showed the inherent toxicity of dyes was primarily dependent on the structure of parent molecule. Upon illumination, the photosensitizers showed obvious phototoxicity to all organisms. The dyes showed stronger phototoxicity to Gram-positive bacteria. With the increasing number of halogen substituents, the singlet oxygen yields increased and the phototoxic activity increased too. There was no obvious correlation between relative lipophilicity and activity in the current study. Our results showed xanthenes had the potential to act as alternatives to conventional antimicrobial compounds and also could be used for the decontamination of microbially polluted waters.
Coagulation kinetics are well established for purified blood proteases or human plasma clotting isotropically. However, less is known about thrombin generation kinetics and transport within blood clots formed under hemodynamic flow. Using microfluidic perfusion (wall shear rate, 200 s ؊1 ) of corn trypsin inhibitor-treated whole blood over a 250-m long patch of type I fibrillar collagen/lipidated tissue factor (TF; ϳ1 TF molecule/ m 2 ), we measured thrombin released from clots using thrombin-antithrombin immunoassay. The majority (>85%) of generated thrombin was captured by intrathrombus fibrin as thrombin-antithrombin was largely undetectable in the effluent unless Gly-Pro-Arg-Pro (GPRP) was added to block fibrin polymerization. With GPRP present, the flux of thrombin increased to ϳ0.5 ؋ 10 ؊12 nmol/m 2 -s over the first 500 s of perfusion and then further increased by ϳ2-3-fold over the next 300 s. The increased thrombin flux after 500 s was blocked by antiFXIa antibody (O1A6), consistent with thrombin-feedback activation of FXI. Over the first 500 s, ϳ92,000 molecules of thrombin were generated per surface TF molecule for the 250-m-long coating. A single layer of platelets (obtained with ␣ IIb  3 antagonism preventing continued platelet deposition) was largely sufficient for thrombin production. Also, the overall thrombin-generating potential of a 1000-m-long coating became less efficient on a per m 2 basis, likely due to distal boundary layer depletion of platelets. Overall, thrombin is robustly generated within clots by the extrinsic pathway followed by late-stage FXIa contributions, with fibrin localizing thrombin via its antithrombin-I activity as a potentially selflimiting hemostatic mechanism.
Introduction Metabolites are underappreciated for their effect on coagulation. Taurocholic acid (TUCA), a bile acid, has been shown to regulate cellular activity and promote fibrin sealant degradation. We hypothesize that TUCA impairs whole blood clot formation and promotes fibrinolysis. Methods TUCA was exogenously added to whole blood obtained from volunteers. A titration from 250 μM to 750 μM was utilized due to biologic relevance. Whole blood mixtures were assayed using thrombelastography (TEG) for clot strength (MA) and fibrinolysis (LY30) quantification. Tranexamic acid (TXA) was used to block plasmin mediated fibrinolysis. Platelet microfluidics were performed. A proteomic analysis was completed on citrated plasma obtained from a shock and resuscitation rat model. Results Fibrinolysis increased, when 750 μM TUCA was added to whole blood (median LY30 0.08 to 5.7, p=0.010), and clot strength decreased (median MA of 53.3 to 43.8, p=0.010). The addition of TXA, to a 750 μM TUCA titration, partially reversed the induced fibrinolysis (LY30: without 7.7 vs. with 2.7) and the decrease in clot strength (MA: without 48.2 vs. with 53.2), but did not reverse the effects to whole blood levels. Platelet function reduced by 50% in the presence of 100 μM TUCA. Rats had a median 52-fold increase in TUCA, following a shock state that stayed elevated following resuscitation. Conclusion TUCA reduces clot strength and promotes fibrinolysis. The clot strength reduction is attributable to platelet inhibition. This metabolic effect on coagulation warrants further investigation, as localized areas of the body, with high levels of bile acid, may be at risk for postoperative bleeding.
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