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J. Biol. Chem., Vol. 279, Issue 38, 39863-39871, September 17, 2004

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Phospholipid Barrier to Fibrinolysis

ROLE FOR THE ANIONIC POLAR HEAD CHARGE AND THE GEL PHASE CRYSTALLINE STRUCTURE^*

Balázs Váradi, Krasimir Kolev, Kiril Tenekedjiev, Gyöngyi Mészáros, Ilona Kovalszky¶, Colin Longstaff||, and Raymund Machovich

From the Department of Medical Biochemistry and the ^¶1st Department of Pathology, Semmelweis University, 1088 Budapest, Hungary and ^||Division of Haematology, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire EN6 3QG, United Kingdom

The massive presence of phospholipids is demonstrated in frozen sections of human arterial thrombi. Purified platelet phospholipids and synthetic phospholipids retard in vitro tissue-type plasminogen activator (tPA)-induced fibrinolysis through effects on plasminogen activation and plasmin function. The inhibition of plasminogen activation on the surface of fibrin correlates with the fraction of anionic phospholipid. The phospholipids decrease the amount of tPA penetrating into the clot by 75% and the depth of the reactive surface layer occupied by the activator by up to 30%, whereas for plasmin both of these parameters decrease by 50%. The phospholipids are not only a diffusion barrier, they also bind the components of the fibrinolytic system. Isothermal titration calorimetry shows binding characterized with dissociation constants in the range 0.35-7.64 µM for plasmin and tPA (lower values with more negative phospholipids). The interactions are endothermic and thermodynamically driven by an increase in entropy, probably caused by the rearrangements in the ordered gel structure of the phospholipids (in line with the stronger inhibition at gel phase temperatures compared with liquid crystalline phase temperatures). These findings show a phospholipid barrier, which should be overcome during lysis of arterial thrombi.

Received for publication, May 10, 2004 , and in revised form, July 14, 2004.

^* This work was supported by Hungarian Scientific Research Grants T031891 and NFKP-1A/0023/2002, Hungarian Ministry of Health Grant ETT288/2000, and Wellcome Trust Grant 069520/Z/02/Z. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Medical Biochemistry, Semmelweis University, Puskin u. 9., H-1088 Budapest, Hungary. Tel.: 36-1-2661030; Fax: 36-12667480; E-mail: kale{at}puskin.sote.hu.

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