title: Suppression of membrane microvesiculation--a possible anticoagulant and anti-tumor progression effect of heparin.
abstract: Heparins (unfractionated and low molecular weight (LMWH) heparins) primarily used as anticoagulants, were found to be effective also in slowing down the development of some types of cancer. On the other hand, the number of microvesicles in the peripheral blood originating from the budding of cell membranes (mostly platelets) is increased in hypercoagulabile states as well as in cancer, indicating a possible common underlying mechanism. It was hypothesized that by mediating an attractive interaction between phospholipid membranes heparin suppresses microvesiculation and thereby acts as an anticoagulant and anti-tumor agent. In this work, the effect of LMWH nadroparin on phospholipid membranes was tested in vitro in a system of giant phospholipid vesicles (GPVs) created by electroformation and observed under the phase contrast microscope. Plasma of different blood donors containing different concentrations of nadroparin was added to the suspension of GPVs to induce adhesion between GPVs. The attractive interaction between membranes was assessed by measuring the average effective angle of contact between the adhered GPVs. It was found in healthy donors, in a donor with gastrointestinal cancer and in a donor with rheumatoid arthritis that adding therapeutic doses of nadroparin to the plasma samples enhanced adhesion of phospholipid membranes in a dose and time-dependent manner while nadroparin alone had no effect within the therapeutic concentration range. The results are in favor of the hypothesis that suppression of microvesiculation underlies both, the anticoagulant and the anti-tumor progression effect of heparin.
authors.affiliation: Laboratory of Clinical Biophysics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Vid
authors.initials: V
authors.lastname: Sustar
authors.forename: Rado
authors.initials: R
authors.lastname: Jansa
authors.forename: Mojca
authors.initials: M
authors.lastname: Frank
authors.forename: Henry
authors.initials: H
authors.lastname: Hagerstrand
authors.forename: Mojca
authors.initials: M
authors.lastname: Krzan
authors.forename: Ales
authors.initials: A
authors.lastname: Iglic
authors.forename: Veronika
authors.initials: V
authors.lastname: Kralj-Iglic
mesh_terms: D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy; D002308:Cardiolipins / Q000737:chemistry; D055252:Cell-Derived Microparticles / Q000187:drug effects*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000097:blood / Q000188:drug therapy; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008297:Male; D008563:Membrane Lipids / Q000737:chemistry; D008858:Microscopy, Phase-Contrast; D008875:Middle Aged; D017762:Nadroparin / Q000494:pharmacology* / Q000627:therapeutic use; D010713:Phosphatidylcholines / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry; D010949:Plasma; D012996:Solutions; D013395:Sucrose / Q000494:pharmacology; D019851:Thrombophilia / Q000097:blood / Q000188:drug therapy* / Q000209:etiology
chemical_list: C519576:1,1',2,2'-tetraoleoylcardiolipin; D000925:Anticoagulants; D000970:Antineoplastic Agents; D002308:Cardiolipins; D008081:Liposomes; D008563:Membrane Lipids; D017762:Nadroparin; D010713:Phosphatidylcholines; D010743:Phospholipids; D012996:Solutions; D013395:Sucrose; C028694:1-palmitoyl-2-oleoylphosphatidylcholine