Abstract
Protamine sulfate (PS) is a polycationic protein drug obtained from the sperm of fish, and is used to reverse the anticoagulant effect of unfractionated heparin (UFH). However, the interactions between PS, UFH, and platelets are still not clear. We measured the platelet numbers and collagen-induced aggregation, P-selectin, platelet factor 4, β-thromboglobulin, prostacyclin metabolite, D-dimers, activated partial thromboplastin time, prothrombin time, anti-factor Xa, fibrinogen, thrombus weight and megakaryocytopoiesis in blood collected from mice and rats in different time points.. All of the groups were treated intravenously with vehicle, UFH, PS, or UFH with PS. We found a short-term antiplatelet activity of PS in mice and rats, and long-term platelet-independent antithrombotic activity in rats with electrically-induced thrombosis. The antiplatelet and antithrombotic potential of PS may contribute to bleeding risk in PS-overdosed patients. The inhibitory effect of PS on the platelets was attenuated by UFH without inducing thrombocytopenia. Treatment with UFH and PS did not affect the formation, number, or activation of platelets, or the thrombosis development in rodents.
Highlights
Protamine sulfate (PS), an alkaline protein consisting mainly of arginine, stabilizes DNA during spermatogenesis
We decided to choose a therapeutic dose of unfractionated heparin (UFH) (150 U/kg) that extended the activated partial thromboplastin time by almost three times and the bleeding time by half in rats [30]
There was no statistical difference in platelet count in the mice treated once a week with UFH and protamine sulfate (PS), or PS alone for 35 days, but we noted a drop in the number of platelets, to below 50%, in three out of the seven mice treated with UFH and PS at the end of the experiment (Figure 1a)
Summary
Protamine sulfate (PS), an alkaline protein consisting mainly of arginine, stabilizes DNA during spermatogenesis. PS is used in medicine to reverse the anticoagulant activity of anionic unfractionated heparin (UFH), and to stabilize neutral protamine Hagedorn (NPH) insulin [1]. PS is currently derived from the sperm nuclei of chum salmon fish, which were traditionally caught at the north-eastern coast of the Japanese island of Honshu. The salmon fishing areas were moved north of the Hokkaido island after the Japan earthquake and tsunami of 2011. PS may induce an anaphylactic reaction in patients receiving NPH insulin or those with a fish allergy, which is probably related to its animal origin. The risk still exists and may increase by both the release of UFH from complexes with PS [3], or with the additional doses of PS [4]
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