Homozygous Deficiency of Heparin Cofactor II

Abstract

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 α1-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.

Residues in the Human Corticosteroid-binding Globulin Reactive Center Loop That Influence Steroid Binding before and after Elastase Cleavage

“…This tight packing of the P17 residue is functionally very important because naturally occurring mutations at P17 in AAT (anti-trypsin Z) (24) and heparin cofactor II (25) disrupt the salt bridge and cause these mutant proteins to polymerize. Thus, the P17 glutamic acid in serpin RCLs has an important stabilizing role, and it is clear that it limits the mobility of the ␤-turn because it is anchored in the same ways in both cleaved and un-cleaved serpins, as illustrated in the native rat CBG (13) and cleaved human CBG-AAT chimera (14) crystal structures.…”

Sulodexide: A Renewed Interest in This Glycosaminoglycan

“…GAGs exert an antithrombotic action by interacting with naturally occurring serine protease inhibitors such as antithrombin III (ATIII) and heparin cofactor II (HCII) (3,17). As a result of these interactions, the inhibition of activated serine proteases in the coagulation cascade by ATIII and HCII is accelerated more than 1000 fold (38,42,69).…”

Heparin Cofactor II is an Independent Protective Factor against Peripheral Arterial Disease in Elderly Subjects with Cardiovascular Risk Factors

“…HC is thought to be able to attenuate the actions of thrombin generated at the injured vascular walls. When the endothelial layer is intact in such young individuals, it is conceivable that the reduction of plasma HC does not influence the manifestation of apparent cardiovascular disorders, except for rare deep vein thrombosis 44) , although the reduction of plasma HC activity in elderly patients with cardiovascular risk factors should aggravate vascular damage, leading to atherosclerotic disorders, including ischemic heart disease and cerebral infarction 41) . In fact, we found a 66-year-old Japanese woman with congenital HC deficiency manifesting as multiple and advanced atherosclerotic lesions 25) .…”