Neutralization of dermatan sulfate in vitro and in vivo by protamine sulfate and polybrene.
The neutralization of the anticoagulant, anti-thrombin, and bleeding effects of dermatan sulfate (DS), a potential antithrombotic agent, was investigated. Protamine sulfate (PS) and hexadimethrine bromide (Polybrene), which reverse the anticoagulant effect of heparin, also neutralized DS in vitro. In human plasma, polybrene was approximately 3 times more active on a weight basis than PS for neutralizing DS (1.5 micrograms polybrene inhibits 1 microgram DS). Intravenous administration of polybrene to rabbits pretreated with DS in a 1:1 weight ratio immediately neutralized 90% of DS and this effect was stable with time. In contrast, PS in a weight ratio of 6:1 (PS to DS) only neutralized 50% of DS injected. When plasma DS concentrations were maintained by continuous infusion between 3 and 15 micrograms/ml, a bolus of polybrene 0.25 mg/kg induced an immediate drop of about 4 micrograms/ml but initial values of DS were recovered within 20 min. PS was again much less effective than polybrene for neutralizing DS. The bleeding effect of DS and its correction by polybrene was studied by using the rat tail transection model. Very large doses of DS (greater than 10 mg/kg) were required to get a modest prolongation of bleeding time. The injection of equivalent doses of polybrene in animals pretreated by DS induced a strong bleeding effect associated with a drop in platelet and leukocyte counts. Animal models are thus inappropriate for investigating the correction of DS-induced bleeding, because high doses of both DS and neutralizing agents are required in these models. Our results indicate that, provided the doses of neutralizing agents remain below their established levels of toxicity in man, DS could if necessary be neutralized completely by polybrene and partially by PS.
Sié
P
P
Laboratoire d'Hémostase, CRTS, Hôpital Purpan, Toulouse, France.
Cremers
B
B
Dupouy
D
D
Caranobe
C
C
Dol
F
F
Boneu
B
B
D000818:Animals; D001780:Blood Coagulation Tests; D002807:Chondroitin / Q000031:analogs & derivatives*; D003871:Dermatan Sulfate / Q000037:antagonists & inhibitors*; D006487:Hemostasis / Q000187:drug effects; D006583:Hexadimethrine Bromide / Q000494:pharmacology*; D008297:Male; D011073:Polyamines / Q000494:pharmacology*; D011479:Protamines / Q000494:pharmacology*; D011817:Rabbits
D011073:Polyamines; D011479:Protamines; D003871:Dermatan Sulfate; D006583:Hexadimethrine Bromide; D002807:Chondroitin