The Inhibitory Effect of Protamine on Platelets is Attenuated by Heparin without Inducing Thrombocytopenia in Rodents

Mar Drugs. 2019 Sep 17;17(9):539. doi: 10.3390/md17090539.


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.

Keywords: animal models; heparin; platelets; protamine; thrombocytopenia; thrombosis.

MeSH terms

  • Animals
  • Anticoagulants / administration & dosage
  • Anticoagulants / adverse effects*
  • Blood Platelets / drug effects
  • Disease Models, Animal
  • Hemorrhage / blood
  • Hemorrhage / chemically induced
  • Hemorrhage / prevention & control
  • Heparin / administration & dosage
  • Heparin / adverse effects*
  • Heparin Antagonists / administration & dosage
  • Heparin Antagonists / adverse effects*
  • Humans
  • Male
  • Mice
  • Partial Thromboplastin Time
  • Platelet Aggregation / drug effects
  • Protamines / administration & dosage
  • Protamines / adverse effects*
  • Rats
  • Thrombocytopenia / blood
  • Thrombocytopenia / chemically induced
  • Thrombocytopenia / diagnosis*
  • Time Factors


  • Anticoagulants
  • Heparin Antagonists
  • Protamines
  • Heparin