Heparanase modulates heparinoids anticoagulant activities via non-enzymatic mechanisms.
A key element for the physiological restriction of blood coagulation at the endothelial cell surface is its non-thrombogenic property, mainly attributed to cell surface heparan sulfate proteoglycans. Heparanase is an endo-beta-D-glucuronidase with specific heparan sulfate degrading activity, which is produced and stored in platelets, and is released upon their activation. We examined the effects of heparanase pro-enzyme on coagulation functions, predominantly under physiological conditions. While heparanase pro-enzyme does not directly affect coagulation protein activities, it has profound effects on heparinoid-mediated regulation of coagulation responses, apparently via mechanisms that do not involve its enzymatic activity. Heparanase pro-enzyme reverses the anti-coagulant activity of unfractionated heparin on the coagulation pathway as well as on thrombin activity. In addition, heparanase pro-enzyme abrogated the factor X inhibitory activity of low-molecular-weight heparin (LMWH). The pro-coagulant effects of the non-active heparanase were also exerted by its major functional heparin-binding peptide. Finally, the effects of heparanase on the activity of factor VII activating protease that is auto-activated by heparinoids indicated a complete antagonistic action of heparanase in this system. Altogether, heparanase pro-coagulant activities that were also demonstrated in plasma samples from patients under LMWH treatment, point to a possible use of this molecule as antagonist for heparinoid treatment.
The Hematology Institute, Tel-Aviv Sourasky Medical Center, Tel-Aviv 64239, Israel. bkatz@tasmc.health.gov.il
Ben-Zion
BZ
Katz
Lars
L
Muhl
Etty
E
Zwang
Neta
N
Ilan
Yair
Y
Herishanu
Varda
V
Deutsch
Elizabeth
E
Naparstek
Israel
I
Vlodavsky
Klaus T
KT
Preissner
D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D005170:Factor X / Q000037:antagonists & inhibitors / Q000378:metabolism; D005966:Glucuronidase / Q000097:blood / Q000378:metabolism*; D006494:Heparin Antagonists / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D006496:Heparinoids / Q000494:pharmacology*; D006801:Humans; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000378:metabolism; D011479:Protamines / Q000494:pharmacology; D011517:Prothrombin Time; D012697:Serine Endopeptidases / Q000097:blood; D013917:Thrombin / Q000378:metabolism; D013918:Thrombin Time; D000099175:Heparanase
D000925:Anticoagulants; D004792:Enzyme Precursors; D005170:Factor X; D005966:Glucuronidase; D006494:Heparin Antagonists; D006495:Heparin, Low-Molecular-Weight; D006496:Heparinoids; D010446:Peptide Fragments; D011479:Protamines; D012697:Serine Endopeptidases; D013917:Thrombin; D000099175:Heparanase; C433550:HABP2 protein, human