Heparin Cofactor II: Discovery, Properties, and Role in Controlling Vascular Homeostasis

Abstract

Heparin cofactor II (HCII) is a serine protease inhibitor (serpin) found in high concentrations in human plasma. Despite its discovery >30 years ago, its physiological function is still poorly understood. It is known to inhibit thrombin, the predominant coagulation protease, and HCII-thrombin complexes have been found in plasma, yet it is thought to contribute little to normal hemostasis. However, thrombin has several other physiological functions, and therefore many biological roles for HCII need consideration. The unique structure and mechanism of action of HCII have helped guide our understanding of HCII. In particular, HCII binds many glycosaminoglycans (GAGs) such as heparin and heparin sulfate as well as several different polyanions to enhance its inhibition of thrombin. Distinctly, HCII is able to use the GAG dermatan sulfate for accelerated thrombin inhibition. Dermatan sulfate is found in high concentrations in the walls of blood vessels as well as in placental tissue. This knowledge has led to research indicating that HCII may play a protective role in atherosclerosis and placental thrombosis. Additionally, pharmaceuticals are being developed that use the dermatan sulfate activation of HCII for anticoagulation. Although much research is still needed to fully understand HCII, this humble protein may have significant impact in our medical future. This article reviews the laboratory history, protein characteristics, structure-activity relationships, protease inhibition, physiological function, and medical relevance of HCII in hopes of regenerating interest in this sometimes forgotten serpin.

Laser Capture Microdissected Mucosa versus Whole Tissue Specimens for Assessment of Radiation-Induced Dynamic Molecular and Pathway Changes in the Small Intestine

“…Pathway analysis revealed a strong activation of the coagulation system, indicative of damage to the endothelial lining of microvessels. The up-regulation of genes coding anticoagulant factors such as Serpinc1 (ATIII) and Serpind1 (heparin cofactor II) may suggest a link of activated anticoagulant factors to intestinal bleeding [12]–[14]. The increased expression of the procoagulant factors F8 [15] and Bdkrb1 [16], [17] as well as an inhibitor of a wide variety of proteases Serpina1 (alpha-1 antiproteinase) [18] could be explained as a compensatory response to achieve a balanced hemostasis and protect the tissue from degradation.…”

Endothelial Cells, Cholesterol, Cytokines, and Aging

“…Vascular endothelium has strategic location between the plasma and the underlying tissue and is an active paracrine, endocrine, and autocrine organ that is indispensable for the regulation of vascular tone and the maintenance of vascular homeostasis (36)(37)(38)(39)(40)(41). Macrophages, fibroblasts, and endothelial cells all move into wounds at the same time.…”

The complete N-terminal extension of heparin cofactor II is required for maximal effectiveness as a thrombin exosite 1 ligand

“…Heparin cofactor II (HCII) is a 66 kDa plasma protein and member of the serpin superfamily of protease inhibitors [1,2] (reviewed in [3]). It regulates the key coagulation protease thrombin by trapping it in a covalently-linked denaturation-resistant complex.…”