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Enhancing clot properties through fibrin-specific self-cross-linked PEG side-chain microgels.

ABSTRACT: Excessive bleeding and resulting complications are a major cause of death in both trauma and surgical settings. Recently, there have been a number of investigations into the design of synthetic hemostatic agents with platelet-mimicking activity to effectively treat patients suffering from severe hemorrhage. We developed platelet-like particles from microgels composed of polymers carrying polyethylene glycol (PEG) side-chains and fibrin-targeting single domain variable fragment antibodies (PEG-PLPs). Comparable to natural platelets, PEG-PLPs were found to enhance the fibrin network formation in vitro through strong adhesion to the emerging fibrin clot and physical, non-covalent cross-linking of nascent fibrin fibers. Furthermore, the mechanical reinforcement of the fibrin mesh through the incorporation of particles into the network leads to a ?three-fold decrease of the overall clot permeability as compared to control clots. However, transport of biomolecules through the fibrin clots, such as peptides and larger proteins is not hindered by the presence of PEG-PLPs and the altered microstructure. Compared to control clots with an elastic modulus of 460+/-260?Pa, PEG-PLP-reinforced fibrin clots exhibit higher degrees of stiffness as demonstrated by the significantly increased average Youn?s modulus of 1770?+/±720?Pa, as measured by AFM force spectroscopy. Furthermore, in vitro degradation studies with plasmin demonstrate that fibrin clots formed in presence of PEG-PLPs withstand hydrolysis for 24?h, indicating enhanced stabilization against exogenous fibrinolysis. The entire set of data suggests that the designed platelet-like particles have high potential for use as hemostatic agents in emergency medicine and surgical settings.

SUBMITTER: Welsch N

PROVIDER: S-EPMC6050065 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Enhancing clot properties through fibrin-specific self-cross-linked PEG side-chain microgels.

Welsch Nicole N Brown Ashley C AC Barker Thomas H TH Lyon L Andrew LA

Colloids and surfaces. B, Biointerfaces 20180302

Excessive bleeding and resulting complications are a major cause of death in both trauma and surgical settings. Recently, there have been a number of investigations into the design of synthetic hemostatic agents with platelet-mimicking activity to effectively treat patients suffering from severe hemorrhage. We developed platelet-like particles from microgels composed of polymers carrying polyethylene glycol (PEG) side-chains and fibrin-targeting single domain variable fragment antibodies (PEG-PL ...[more]

PMID: 29549720

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Project description:BackgroundRecent studies suggest that adult-specific treatment options for fibrinogen replacement during bleeding may be less effective in neonates. This is likely due to structural and functional differences found in the fibrin network between adults and neonates. In this investigation, the authors performed a comparative laboratory-based study between immature and adult human and porcine plasma samples in order to determine if piglets are an appropriate animal model of neonatal coagulopathy.MethodsAdult and neonatal human and porcine plasma samples were collected from the Children's Hospital of Atlanta and North Carolina State University College of Veterinary Medicine, respectively. Clots were formed for analysis and fibrinogen concentration was quantified. Structure was examined through confocal microscopy and cryogenic scanning electron microscopy. Function was assessed through atomic force microscopy nanoindentation and clotting and fibrinolysis assays. Lastly, novel hemostatic therapies were applied to neonatal porcine samples to simulate treatment.ResultsAll sample groups had similar plasma fibrinogen concentrations. Neonatal porcine and human plasma clots were less branched with lower fiber densities than the dense and highly branched networks seen in adult human and porcine clots. Neonatal porcine and human clots had faster degradation rates and lower clot stiffness values than adult clots (stiffness [mmHg] mean ± SD: neonatal human, 12.15 ± 1.35 mmHg vs. adult human, 32.25 ± 7.13 mmHg; P = 0.016; neonatal pig, 10.5 ± 8.25 mmHg vs. adult pigs, 32.55 ± 7.20 mmHg; P = 0.015). The addition of hemostatic therapies to neonatal porcine samples enhanced clot formation.ConclusionsThe authors identified similar age-related patterns in structure, mechanical, and degradation properties between adults and neonates in porcine and human samples. These findings suggest that piglets are an appropriate preclinical model of neonatal coagulopathy. The authors also show the feasibility of in vitro model application through analysis of novel hemostatic therapies as applied to dilute neonatal porcine plasma.

Project description:Background: Mechanisms by which chronic kidney disease (CKD) influences fibrin clot properties in atrial fibrillation (AF) remain ill-defined. We aimed to investigate the effects of AF and CKD on fibrin clot properties and lipoproteins, and determine the relationship between these factors. Methods: Prospective cross-sectional study of patients recruited from cardiology services in Liverpool between September 2019 and October 2021. Primary groups consisted of anticoagulated AF patients with and without CKD in a 1:1 ratio. Control group comprised anticoagulated patients without AF or CKD. Fibrin clot properties were analysed using turbidity and permeation assays. Detailed lipoprotein characteristics, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), small dense LDL and oxidised LDL, were measured. Results: Fifty-six anticoagulated patients were enrolled (median age 72.5; 34% female); 46 with AF (23 with CKD and 23 without CKD) and 10 controls. AF was associated with changes in three indices of fibrin clot properties using PTT (Tlag 314 vs. 358 s, p = 0.047; Abspeak 0.153 vs. 0.111 units, p = 0.031; Tlysis50% 884 vs. 280 s, p = 0.047) and thrombin reagents (Tlag 170 vs. 132 s, p = 0.031; Tmax 590 vs. 462 s, p = 0.047; Tpeak50% 406 vs. 220 s, p = 0.005) while the concomitant presence of CKD led to changes in fibrin clot properties using kaolin (Tlag 1072 vs. 1640 s, p = 0.003; Tmax 1458 vs. 1962 s, p = 0.005; Tpeak50% 1294 vs. 2046, p = 0.008) and PPP reagents (Tlag 566 vs. 748 s, p = 0.044). Neither of these conditions were associated with changes in fibrin clot permeability. Deteriorating eGFR was significantly correlated to the speed of clot formation, and CKD was independently associated with unfavourable clot properties (Tlag -778, p = 0.002; Tmax -867, p = 0.004; Tpeak50% -853, p = 0.004 with kaolin reagent). AF alone was not associated with changes in lipoprotein distribution while AF patients with CKD had lower total cholesterol, LDL-C and small dense LDL due to the presence of other risk factors. No significant relationship was observed between fibrin clot properties and lipoprotein distribution. Conclusions: There are important changes that occur in fibrin clot properties with AF and CKD that may account for the increased risk of thromboembolic complications. However, these changes in fibrin clot properties were not attributable to alterations in lipoprotein distribution.

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Enhancing clot properties through fibrin-specific self-cross-linked PEG side-chain microgels.

Publications

Enhancing clot properties through fibrin-specific self-cross-linked PEG side-chain microgels.

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