Dataset Information

Clot-targeted magnetic hyperthermia permeabilizes blood clots to make them more susceptible to thrombolysis.

ABSTRACT:

Background

Thrombolysis is a frontline treatment for stroke, which involves the application of tissue plasminogen activator (tPA) to trigger endogenous clot-degradation pathways. However, it is only effective within 4.5 h of symptom onset because of clot contraction preventing tPA permeation into the clot. Magnetic hyperthermia (MH) mediated by tumor-targeted magnetic nanoparticles is used to treat cancer by using local heat generation to trigger apoptosis of cancer cells.

Objectives

To develop clot-targeting magnetic nanoparticles to deliver MH to the surface of human blood clots, and to assess whether this can improve the efficacy of thrombolysis of contracted blood clots.

Methods

Clot-targeting magnetic nanoparticles were developed by functionalizing iron oxide nanoparticles with an antibody recognizing activated integrin αIIbβ3 (PAC-1). The magnetic properties of the PAC-1-tagged magnetic nanoparticles were characterized and optimized to deliver clot-targeted MH.

Results

Clot-targeted MH increases the efficacy of tPA-mediated thrombolysis in contracted human blood clots, leading to a reduction in clot weight. MH increases the permeability of the clots to tPA, facilitating their breakdown. Scanning electron microscopy reveals that this effect is elicited through enhanced fibrin breakdown and triggering the disruption of red blood cells on the surface of the clot. Importantly, endothelial cells viability in a three-dimensional blood vessel model is unaffected by exposure to MH.

Conclusions

This study demonstrates that clot-targeted MH can enhance the thrombolysis of contracted human blood clots and can be safely applied to enhance the timeframe in which thrombolysis is effective.

SUBMITTER: Cabrera D

PROVIDER: S-EPMC9826519 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

Clot-targeted magnetic hyperthermia permeabilizes blood clots to make them more susceptible to thrombolysis.

Cabrera David D Eizadi Sharifabad Maneea M Ranjbar Jacob A JA Telling Neil D ND Harper Alan G S AGS

Journal of thrombosis and haemostasis : JTH 20220902 11

<h4>Background</h4>Thrombolysis is a frontline treatment for stroke, which involves the application of tissue plasminogen activator (tPA) to trigger endogenous clot-degradation pathways. However, it is only effective within 4.5 h of symptom onset because of clot contraction preventing tPA permeation into the clot. Magnetic hyperthermia (MH) mediated by tumor-targeted magnetic nanoparticles is used to treat cancer by using local heat generation to trigger apoptosis of cancer cells.<h4>Objectives< ...[more]

PMID: 35950914

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Project description:IntroductionTrauma-induced coagulopathy is a continuum ranging from hypercoagulable to hypercoagulable phenotypes. In single-center studies, the maximum amplitude (MA) to r-time (R) (MA-R) ratio has identified a phenotype of injured patients with high mortality risk. The purpose of this study was to determine the relationship between MA-R and mortality using multicenter data and to investigate fibrinogen consumption in the development of this specific coagulopathy phenotype.MethodsUsing the Pragmatic Randomized Optimal Platelet and Plasma Ratios data set, patients were divided into blunt and penetrating injury cohorts. MA was divided by R time from admission thromboelastogram to calculate MA-R. MA-R was used to assess odds of early and late mortality using multivariable models. Multivariable models were used to assess thrombogram values in both cohorts. Refinement of the MA-R cut point was performed with Youden index. Repeat multivariable analysis was performed with a binary CRITICAL and NORMAL MA-R.ResultsIn initial analysis, MA-R quartiles were not associated with mortality in the penetrating cohort. In the blunt cohort, there was an association between low MA-R and early and late mortality. A refined cut point of 11 was identified (CRITICAL: MA-R, ≤11; NORMAL: MA-R, >11). CRITICAL MA-R was associated with mortality in both penetrating and blunt subgroups. In further injury subgroup analysis, CRITICAL patients had significantly decreased fibrinogen levels in the blunt subgroup only. In both blunt and penetrating injury, there was no difference in time to initiation of thrombin burst (lagtime). However, both endogenous thrombin potential and peak thrombin levels were significantly lower in CRITICAL patients.ConclusionsMA-R identifies a trauma-induced coagulopathy phenotype characterized in blunt injury by impaired thrombin generation that is associated with early and late mortality. The endotheliopathy and tissue factor release likely plays a role in the cascade of impaired thrombin burst, possible early fibrinogen consumption and the weaker clot identified by MA-R.Level of evidenceTherapeutic/care management, level II.

Project description:Fibrinolytics such as recombinant tissue plasminogen activator (rt-PA) are used to treat thrombotic disease such as acute myocardial infarction (AMI) and ischemic stroke. Interest in increasing efficacy and reducing side effects has led to the study of adjuncts such as GP IIb-IIIa inhibitors and ultrasound (US) enhanced thrombolysis. Currently, GP IIb-IIIa inhibitor and fibrinolytic treatment are often used in AMI, and are under investigation for stroke treatment. However, little is known of the efficacy of combined GP IIb-IIIa inhibitor, fibrinolytic and ultrasound treatment. We measure the lytic efficacy of rt-PA, eptifibatide (Epf) and 120 kHz ultrasound treatment in an in-vitro human clot model.Blood was drawn from 15 subjects after IRB approval. Clots were made in 20 microL pipettes, and placed in a water tank for microscopic visualization during lytic treatment. Clots were exposed to control, rt-PA (rt-PA), eptifibatide (Epf), or rt-PA+eptifibatide (rt-PA + Epf), with (+US) or without (-US) ultrasound for 30 minutes at 37 degrees C in human plasma. Clot lysis was measured over time, using a microscopic imaging technique. The fractional clot loss (FCL) and initial lytic rate (LR) were used to quantify lytic efficacy.LR values for (- US) treated clots were 0.8+/-0.1(control), 1.8+/-0.3 (Epf), 1.5+/-0.2 (rt-PA), and 1.3+/-0.4 (rt-PA + Epf) (% clot width/minute) respectively. In comparison, the (+ US) group exhibited LR values of 1.6+/-0.2 (control), 4.3+/-0.4 (Epf), 6.3+/-0.4 (rt-PA), and 4.6+/-0.6 (rt-PA + Epf). For (- US) treated clots, FCL was 6.0+/-0.8 (control), 9.2+/-2.5 (Epf), 15.6+/-1.7 (rt-PA), and 28.0+/-2.2% (rt-PA + Epf) respectively. FCL for (+ US) clots was 13.5+/-2.4 (control), 20.7+/-6.4 (Epf), 44.4+/-3.6 (rt-PA) and 30.3+/-3.6% (rt-PA + Epf) respectively. Although the addition of eptifibatide enhances the in-vitro lytic efficacy of rt-PA in the absence of ultrasound, the efficacy of ultrasound and rt-PA is greater than that of combined ultrasound, rt-PA and eptifibatide exposure.

Dataset Information

Clot-targeted magnetic hyperthermia permeabilizes blood clots to make them more susceptible to thrombolysis.

Background

Objectives

Methods

Results

Conclusions

Publications

Clot-targeted magnetic hyperthermia permeabilizes blood clots to make them more susceptible to thrombolysis.

Similar Datasets

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