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Evaluation of Immunostimulatory Potential of Branded and US-Generic Enoxaparins in an In Vitro Human Immune System Model.

Luna E, Agrawal P, Mehta R, Vernhes C, Viskov C, Amiral J, Warren WL, Drake DR - Clin. Appl. Thromb. Hemost. (2014)

Bottom Line: Low-molecular-weight heparins (LMWHs) have several positive therapeutic effects and can also form immunostimulatory complexes with plasma proteins, such as platelet factor 4 (PF4).Production of tissue factor pathway inhibitor (TFPI), a physiologic heparin-induced inhibitor of tissue factor-induced coagulation that was used as a functional readout of biological activity of enoxaparins in these assays, was heightened in the presence of branded enoxaparin complexes, but its levels were variable in cultures treated with complexes containing US-generic enoxaparins.Analytical analyses suggest that the heightened immunostimulatory potential of some of the US-generic enoxaparin product lots could be tied to their capacity to form ultra-large and/or more stable complexes with PF4 than the other LMWHs included in this study.

View Article: PubMed Central - PubMed

Affiliation: Sanofi Pasteur, VaxDesign Campus, Orlando, FL, USA.

No MeSH data available.


Related in: MedlinePlus

TFPI production is inversely correlated with APC activation in MIMIC® PTE assays. MIMIC® PTE assays were treated with PF4 complexes prepared with variant heparinoids. A, APC activation, as measured by CD83 expression (CD14+HLA-DR+ DCs), is shown graphically for all samples included in the assay. B, TFPI secretion, represented as a percentage-change compared with the no-treatment condition, is displayed for the indicated treatment conditions. The data show the mean ± SD for 10 donors examined in 4 distinct experiments. Ag indicates antigen; APC, antigen-presenting cells; DCs, dendritic cells; MIMIC® PTE, Modular IMmune In vitro Construct system-peripheral tissue equivalent; PF4, platelet factor 4; SD, standard deviation; TFPI, tissue factor pathway inhibitor; UFH, unfractionated heparin.
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fig5-1076029614562037: TFPI production is inversely correlated with APC activation in MIMIC® PTE assays. MIMIC® PTE assays were treated with PF4 complexes prepared with variant heparinoids. A, APC activation, as measured by CD83 expression (CD14+HLA-DR+ DCs), is shown graphically for all samples included in the assay. B, TFPI secretion, represented as a percentage-change compared with the no-treatment condition, is displayed for the indicated treatment conditions. The data show the mean ± SD for 10 donors examined in 4 distinct experiments. Ag indicates antigen; APC, antigen-presenting cells; DCs, dendritic cells; MIMIC® PTE, Modular IMmune In vitro Construct system-peripheral tissue equivalent; PF4, platelet factor 4; SD, standard deviation; TFPI, tissue factor pathway inhibitor; UFH, unfractionated heparin.

Mentions: The follow-up study reproduced what was found in the blinded study: (1) PF4–heparin complexes prepared for the blinded study gave identical results in the new 10-donor study group, (2) fresh complexes prepared with a new batch of PF4 and the Lot 2 branded and generic enoxaparins generated the same results as those obtained in the blinded study, and (3) the strong negative correlation between APC activation and TFPI production in the blinded study was confirmed in this set of experiments. As can be seen in the graphs in Figure 5A and B, the 3 batches of PF4–branded enoxaparin, prepared using 2 different enoxaparin lots, were highly consistent in terms of immunostimulatory profiles and capacity to augment TFPI production. Conversely, there were clear differences between the 2 US-generic enoxaparin product lots regarding their capacity to trigger immune cell activation and modulate TFPI production (Figure 5A and B). The results of the blinded and follow-up studies were integrated together into Table 4 to show the differential response profiles of PF4 complexes prepared with branded and US-generic enoxaparins.


Evaluation of Immunostimulatory Potential of Branded and US-Generic Enoxaparins in an In Vitro Human Immune System Model.

Luna E, Agrawal P, Mehta R, Vernhes C, Viskov C, Amiral J, Warren WL, Drake DR - Clin. Appl. Thromb. Hemost. (2014)

TFPI production is inversely correlated with APC activation in MIMIC® PTE assays. MIMIC® PTE assays were treated with PF4 complexes prepared with variant heparinoids. A, APC activation, as measured by CD83 expression (CD14+HLA-DR+ DCs), is shown graphically for all samples included in the assay. B, TFPI secretion, represented as a percentage-change compared with the no-treatment condition, is displayed for the indicated treatment conditions. The data show the mean ± SD for 10 donors examined in 4 distinct experiments. Ag indicates antigen; APC, antigen-presenting cells; DCs, dendritic cells; MIMIC® PTE, Modular IMmune In vitro Construct system-peripheral tissue equivalent; PF4, platelet factor 4; SD, standard deviation; TFPI, tissue factor pathway inhibitor; UFH, unfractionated heparin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2 - License 3
Show All Figures
getmorefigures.php?uid=PMC4401814&req=5

fig5-1076029614562037: TFPI production is inversely correlated with APC activation in MIMIC® PTE assays. MIMIC® PTE assays were treated with PF4 complexes prepared with variant heparinoids. A, APC activation, as measured by CD83 expression (CD14+HLA-DR+ DCs), is shown graphically for all samples included in the assay. B, TFPI secretion, represented as a percentage-change compared with the no-treatment condition, is displayed for the indicated treatment conditions. The data show the mean ± SD for 10 donors examined in 4 distinct experiments. Ag indicates antigen; APC, antigen-presenting cells; DCs, dendritic cells; MIMIC® PTE, Modular IMmune In vitro Construct system-peripheral tissue equivalent; PF4, platelet factor 4; SD, standard deviation; TFPI, tissue factor pathway inhibitor; UFH, unfractionated heparin.
Mentions: The follow-up study reproduced what was found in the blinded study: (1) PF4–heparin complexes prepared for the blinded study gave identical results in the new 10-donor study group, (2) fresh complexes prepared with a new batch of PF4 and the Lot 2 branded and generic enoxaparins generated the same results as those obtained in the blinded study, and (3) the strong negative correlation between APC activation and TFPI production in the blinded study was confirmed in this set of experiments. As can be seen in the graphs in Figure 5A and B, the 3 batches of PF4–branded enoxaparin, prepared using 2 different enoxaparin lots, were highly consistent in terms of immunostimulatory profiles and capacity to augment TFPI production. Conversely, there were clear differences between the 2 US-generic enoxaparin product lots regarding their capacity to trigger immune cell activation and modulate TFPI production (Figure 5A and B). The results of the blinded and follow-up studies were integrated together into Table 4 to show the differential response profiles of PF4 complexes prepared with branded and US-generic enoxaparins.

Bottom Line: Low-molecular-weight heparins (LMWHs) have several positive therapeutic effects and can also form immunostimulatory complexes with plasma proteins, such as platelet factor 4 (PF4).Production of tissue factor pathway inhibitor (TFPI), a physiologic heparin-induced inhibitor of tissue factor-induced coagulation that was used as a functional readout of biological activity of enoxaparins in these assays, was heightened in the presence of branded enoxaparin complexes, but its levels were variable in cultures treated with complexes containing US-generic enoxaparins.Analytical analyses suggest that the heightened immunostimulatory potential of some of the US-generic enoxaparin product lots could be tied to their capacity to form ultra-large and/or more stable complexes with PF4 than the other LMWHs included in this study.

View Article: PubMed Central - PubMed

Affiliation: Sanofi Pasteur, VaxDesign Campus, Orlando, FL, USA.

No MeSH data available.


Related in: MedlinePlus