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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1232.)
© 2002 American Heart Association, Inc.

Thrombosis

Lp(a) Particles Mold Fibrin-Binding Properties of Apo(a) in Size-Dependent Manner

A Study With Different-Length Recombinant Apo(a), Native Lp(a), and Monoclonal Antibody

Chantal Kang^*; Miguel Dominguez^*; Stéphane Loyau; Toshiyuki Miyata; Vincent Durlach; Edouard Anglés-Cano

From INSERM U460 (C.K., M.D, S.L., E.A.-C.), Faculté de Médecine Xavier Bichat, Paris, France; the Laboratory of Thrombosis Research (T.M.), National Cardiovascular Center Research Institute, Osaka, Japan; and Service Endocrinologie-Diabetologie (V.D.), Centre Hospitalo-Universitaire de Reims, Reims, France.

Correspondence to Dr E. Anglés-Cano, INSERM U460, UFR de Médecine Xavier-Bichat, 16 rue Henri Huchard–BP 416, F-75870-Cedex 18, Paris, France.

Objective— Small-sized apolipoprotein(a) [apo(a)] isoforms with high antifibrinolytic activity are frequently found in cardiovascular diseases, suggesting a role for apo(a) size in atherothrombosis. To test this hypothesis, we sought to characterize the lysine (fibrin)-binding function of isolated apo(a) of variable sizes.

Methods and Results— Recombinant apo(a) [r-apo(a)] preparations consisting of 10 to 34 kringles and a monoclonal antibody that neutralizes the lysine-binding function were produced and used in parallel with lipoprotein(a) [Lp(a)] particles isolated from plasma in fibrin-binding studies. All r-apo(a) preparations displayed similar affinity and specificity for lysine residues on fibrin regardless of size (K_d 3.6±0.3 nmol/L) and inhibited the binding of plasminogen with a similar intensity (IC₅₀ 16.8±5.4 nmol/L). In contrast, native Lp(a) particles displayed fibrin affinities that were in inverse relationship with the apo(a) kringle number. Thus, a 15-kringle apo(a) separated from Lp(a) and a 34-kringle r-apo(a) displayed an affinity for fibrin that was higher than that in the corresponding particles (K_d 2.5 versus 10.5 nmol/L and K_d 3.8 versus 541 nmol/L, respectively). However, fibrin-binding specificity of the r-apo(a) preparations and the Lp(a) particles was efficiently neutralized (IC₅₀ 0.07 and 4 nmol/L) by a monoclonal antibody directed against the lysine-binding function of kringle IV-10.

Conclusions— Our data indicate that fibrin binding is an intrinsic property of apo(a) modulated by the composite structure of the Lp(a) particle.

Key Words: lipoprotein(a) • apolipoprotein(a) • plasminogen • fibrin surfaces • fibrin affinity

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