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(Circulation. 2004;110:1303-1307.)
© 2004 American Heart Association, Inc.

Original Articles

Homozygous Deficiency of Heparin Cofactor II

Relevance of P17 Glutamate Residue in Serpins, Relationship With Conformational Diseases, and Role in Thrombosis

Javier Corral, PhD; Justo Aznar, PhD; Rocio Gonzalez-Conejero, PhD; Piedad Villa, BSC; Antonia Miñano, T; Amparo Vayá, MD; Robin W. Carrell, PhD; James A. Huntington, PhD; Vicente Vicente, PhD

From the University of Murcia, Centro Regional de Hemodonación de Murcia, Murcia, Spain (J.C., R.G.-C., A.M., V.V.); Department of Clinical Pathology, La Fe University Hospital, Valencia, Spain (J.A., P.V., A.V.); and CIMR, University of Cambridge, Cambridge, UK (R.W.C., J.A.H.).

Correspondence to Dr Javier Corral, Centro Regional de Hemodonación, Ronda de Garay S/N, Murcia 30003, Spain. E-mail javier.corral{at}carm.es

Received December 18, 2003; de novo received February 19, 2004; revision received April 20, 2004; accepted April 21, 2004.

Background— Heparin cofactor II (HCII) is a hepatic serpin with significant antithrombin activity that has been implicated in coagulation, inflammation, atherosclerosis, and wound repair. Recent data obtained in mice lacking HCII suggest that this serpin might inhibit thrombosis in the arterial circulation. However, the clinical relevance and molecular mechanisms associated with deficiency of HCII in humans are unclear.

Methods and Results— We studied the first family with homozygous HCII deficiency, identifying a Glu428Lys mutation affecting a conserved glutamate at the hinge (P17) of the reactive loop. No carrier reported arterial thrombosis, and only 1 homozygous HCII-deficient patient developed severe deep venous thrombosis, but she also had a de novo Glu100Stop nonsense truncation in the antithrombin gene.

Conclusions— Our results confirm the key structural role of the P17 glutamate in serpins. The same mutation causes conformational instability and polymerization in 3 serpins: Drosophila necrotic, human 1-antitrypsin, and human HCII, which explains their plasma deficiency. In the family under study here, however, plasma HCII deficiency was not associated with a significant clinical phenotype.

Key Words: coagulation • genetics • proteins • risk factors • thrombosis

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