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Fibrin-modulating nanogels for treatment of disseminated intravascular coagulation.

Publication ,  Journal Article
Mihalko, EP; Sandry, M; Mininni, N; Nellenbach, K; Deal, H; Daniele, M; Ghadimi, K; Levy, JH; Brown, AC
Published in: Blood Adv
February 9, 2021

Disseminated intravascular coagulation (DIC) is a pathological coagulopathy associated with infection that increases mortality. In DIC, excessive thrombin generation causes symptoms from formation of microthrombi to multiorgan failure; bleeding risks can also be a concern because of clotting factor consumption. Different clinical events lead to DIC, including sepsis, trauma, and shock. Treatments for thrombotic episodes or bleeding presentation in DIC oppose each other, thus creating therapeutic dilemmas in management. The objective of this study was to develop fibrin-specific core-shell nanogels (FSNs) loaded with tissue-type plasminogen activator (tPA) to treat the microcirculatory complications of DIC, which would facilitate targeted clot dissolution to manage microthrombi and the potential consumptive coagulopathy that causes bleeding. FSNs enhance formation of actively polymerizing clots by crosslinking fibrin fibers, but they can also target preexisting microthrombi and, when loaded with tPA, facilitate targeted delivery to lyse the microthrombi. We hypothesized that this dual action would simultaneously address bleeding and microthrombi with DIC to improve outcomes. In vivo, tPA-FSNs decreased the presentation of multiorgan microthrombi, recovered platelet counts, and improved bleeding outcomes in a DIC rodent model. When incorporated with human DIC patient plasma, tPA-FSNs restored clot structure and clot growth under flow. Together, these data demonstrate that a fibrinolytic agent loaded into fibrin-targeting nanogels could improve DIC outcomes.

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Published In

Blood Adv

DOI

EISSN

2473-9537

Publication Date

February 9, 2021

Volume

5

Issue

3

Start / End Page

613 / 627

Location

United States

Related Subject Headings

  • Thrombosis
  • Nanogels
  • Microcirculation
  • Humans
  • Fibrin
  • Disseminated Intravascular Coagulation
  • 3201 Cardiovascular medicine and haematology
 

Citation

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MLA
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Mihalko, E. P., Sandry, M., Mininni, N., Nellenbach, K., Deal, H., Daniele, M., … Brown, A. C. (2021). Fibrin-modulating nanogels for treatment of disseminated intravascular coagulation. Blood Adv, 5(3), 613–627. https://doi.org/10.1182/bloodadvances.2020003046
Mihalko, Emily P., Megan Sandry, Nicholas Mininni, Kimberly Nellenbach, Halston Deal, Michael Daniele, Kamrouz Ghadimi, Jerrold H. Levy, and Ashley C. Brown. “Fibrin-modulating nanogels for treatment of disseminated intravascular coagulation.Blood Adv 5, no. 3 (February 9, 2021): 613–27. https://doi.org/10.1182/bloodadvances.2020003046.
Mihalko EP, Sandry M, Mininni N, Nellenbach K, Deal H, Daniele M, et al. Fibrin-modulating nanogels for treatment of disseminated intravascular coagulation. Blood Adv. 2021 Feb 9;5(3):613–27.
Mihalko, Emily P., et al. “Fibrin-modulating nanogels for treatment of disseminated intravascular coagulation.Blood Adv, vol. 5, no. 3, Feb. 2021, pp. 613–27. Pubmed, doi:10.1182/bloodadvances.2020003046.
Mihalko EP, Sandry M, Mininni N, Nellenbach K, Deal H, Daniele M, Ghadimi K, Levy JH, Brown AC. Fibrin-modulating nanogels for treatment of disseminated intravascular coagulation. Blood Adv. 2021 Feb 9;5(3):613–627.

Published In

Blood Adv

DOI

EISSN

2473-9537

Publication Date

February 9, 2021

Volume

5

Issue

3

Start / End Page

613 / 627

Location

United States

Related Subject Headings

  • Thrombosis
  • Nanogels
  • Microcirculation
  • Humans
  • Fibrin
  • Disseminated Intravascular Coagulation
  • 3201 Cardiovascular medicine and haematology