Neutralization of low molecular weight heparin by polybrene prevents thromboxane release and severe pulmonary hypertension in awake sheep.

Abstract

Protamine reversal of heparin anticoagulation in patients is occasionally associated with life-threatening acute pulmonary hypertension. In a sheep model, we evaluated the effect on this adverse cardiopulmonary reaction of modifying the type of heparin (low molecular weight heparin compared with unfractionated heparin) and the type of heparin antagonist (polybrene compared with protamine). Protamine reversal of low molecular weight heparin (LMWI) and polybrene reversal of unfractionated heparin induced more than a 10-fold increase of plasma thromboxane B2 levels, a threefold increase of pulmonary vascular resistance and pulmonary artery pressure, and a 25% decrease of Pao2. A similar adverse reaction followed protamine reversal of conventional unfractionated heparin. However, with polybrene (1 mg/lkg) reversal of LMWH (1 mg/kg), we measured neither pulmonary hypertension (pulmonary artery pressure was 22.6±3.6 mm Hg at 1 minute after polybrene reversal of LMWH compared with 47.9±4.2 mm Hg after protamine reversal of unfractionated heparin, p<O.O05 groups differ), hypoxemia (Pao2 was unchanged 2 minutes after polybrene compared with a decrease of 26 mm Hg 2 minutes after protamine, p<0.05), nor acute release of thromboxane into arterial plasma (thromboxane B2 was 0.2±+ 0.1 at 1 minute after polybrene compared with 3.7± 1.7 ng/ml at 1 minute after protamine, p<0.005). The hemodynamic effects and mediator release were also benign after neutralization of larger doses of LIWH (3 mg/kg) by polybrene (3 mg/kg). The increases of activated clotting time and activated partial thromboplastin time due to both types of heparin were completely reversed with polybrene. Anti-Xa activity increased to more than 3 IU/ml 4 minutes after LMWH anticoagulation (p<0.01) but was only partially neutralized by polybrene. Various polyanion-polycation complexes that are formed when heparin anticoagulation is reversed induce thromboxane release and acute pulmonary vasoconstriction in awake sheep. Reversal of LMWH anticoagulation with polybrene does not elicit this adverse reaction. (Circulation 1990;82:1754-1764 P rotamine is widely used to reverse heparin anticoagulation in patients after cardiopulmonary bypass, cardiac catheterization, and vascular surgery. Protamine causes occasionally cat-

Allosteric inhibition of factor XIa. Sulfated non-saccharide glycosaminoglycan mimetics as promising anticoagulants

“…To assess whether FXIa inhibition by SPGG2 can be reversed, we studied protamine, polybrene and SOS. Protamine is a clinically used arginine-rich polypeptide that counteracts the anticoagulant activity of UFH and LMWHs [29], whereas polybrene is a quaternary amine-containing hydrophobic polymer, which has been explored as a probe of electrostatic interactions [30]. SOS is an FDA approved antacid that is known to bind in heparin-binding sites on proteins such as thrombin [31].…”

Thromboxane receptor blockade prevents pulmonary hypertension induced by heparin-protamine reactions in awake sheep.

“…Furthermore, thromboxane release into plasma was similar when heparinprotamine challenges were repeated at 90-minute intervals ( Figure 6) as reported in another study from our laboratory demonstrating that the course and magnitude of plasma thromboxane increase and pulmonary hypertension were not altered when heparinprotamine challenges were repeated at short-term intervals. 18 Fehr and Rohr,28 who demonstrated that administration of cobra venom factor to rabbits, associated with depletion of complement, prevented leukopenia during subsequent heparin-protamine challenges. Thus, although complement activation and pulmonary leukosequestration are consistent events during the heparin-protamine reaction, they do not appear to play a direct role in producing pulmonary vasoconstriction.…”

Protamine and protamine-insulins exacerbate the vascular response to injury.

“…There is already significant concern with the continued use of protamine for reversal of systemic heparinization (40-43). Protamine reactions include hypotension and vascular collapse (12), as well as effects on hematologic and pulmonary function (40, 41,43,44). Our study might add the potential for exacerbation of proliferative vascular disease to this list.…”