Studies on Tissue Factor Pathway Inhibitor Antigen Release by Bovine, Ovine and Porcine Heparins Following Intravenous Administration to Non-Human Primates

Kouta, Ahmed; Hoppensteadt, Debra; Bontekoe, Emily; Jeske, Walter; Duff, Richard; Cera, Lee; Fareed, Jawed

doi:10.1177/1076029620951851

Cited by 2 publications

(2 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…reported a marked increase of TFPI release (~2.5-fold) within 20 min after intravenous administration of different types of heparins (bovine, ovine, and porcine) to non-human primates. 43 Additionally, our observation with different species, including mice, rats, and rabbits ( unpublished data ) are consistent with these results.…”

Section: Discussionsupporting

confidence: 86%

Sulfated non-anticoagulant heparin derivative modifies intracellular hemoglobin, inhibits cell sickling in vitro, and prolongs survival of sickle cell mice under hypoxia

et al. 2021

View full text Add to dashboard Cite

Sickle cell disease (SCD) is an autosomal recessive genetic disease caused by a single point mutation, resulting in abnormal sickle hemoglobin (HbS). During hypoxia or dehydration, HbS polymerizes to form insoluble aggregates and induces sickling of red blood cells (RBCs). RBC sickling increases adhesiveness of RBCs to alter the rheological properties of the blood and triggers inflammatory responses, leading to hemolysis and vaso-occlusive crisis sequelae. Unfractionated heparin (UFH) and low-molecular weight heparins (LMWH) have been suggested as treatments to relieve coagulation complications in SCD. However, they are associated with bleeding complications after repeated dosing. An alternative sulfated nonanticoagulant heparin derivative (S-NACH) was previously reported to have none to low systemic anticoagulant activity and no bleeding side effects, and it interfered with P-selectindependent binding of sickle cells to endothelial cells, with concomitant decrease in the levels of adhesion biomarkers in SCD mice. S-NACH has been further engineered and structurally enhanced to bind with and modify HbS to directly inhibit sickling, thus employing a multimodal approach. Here, we show that S-NACH can (i) directly engage in Schiff-base reactions with HbS to decrease RBC sickling under both normoxia and hypoxia in vitro, ii) prolong the survival of SCD mice under hypoxia, and (iii) regulate the altered steady state levels of pro- and antiinflammatory cytokines. Thus, our proof of concept in vitro and in vivo preclinical studies demonstrate that the multimodal S-NACH is a highly promising candidate for development into an improved and optimized alternative to LMWHs for the treatment of patients with SCD.

show abstract

Section: Discussionsupporting

confidence: 86%

Sulfated non-anticoagulant heparin derivative modifies intracellular hemoglobin, inhibits cell sickling in vitro, and prolongs survival of sickle cell mice under hypoxia

et al. 2021

View full text Add to dashboard Cite

show abstract

“…However, in a primate model, 0.5 mg/kg protamine was adequate to neutralize UFH at either 0.5 mg/kg or 100 units/kg (Kouta et al, 2021). Like PMH, BMH and OMH can inhibit the extrinsic coagulation pathway and release tissue factor pathway inhibitor (TFPI) to an equivalent extent in terms of units of anticoagulant activity rather than by mass, when measured in vivo (Kouta et al, 2020). Relatively little work has been reported on the capacity of heparin of non-porcine origin to cause adverse side-effects, although a physicochemical study has shown that lower concentrations of OMH are required to form large platelet factor 4 (PF4)/heparin complexes (that are believed to cause HIT q.v.)…”

Section: Heparin From Bovine and Other Nonporcine Sourcesmentioning

confidence: 99%