Does Heparin Cofactor II Modulate Atherosclerosis and Restenosis?

Abstract

H eparin cofactor II (HCII) is a plasma protein in search of a physiological function. 1 HCII inactivates thrombin by formation of a stable, bimolecular complex. Detection of these complexes in human plasma suggests that HCII inhibits thrombin in vivo. 2 Sulfated polysaccharides such as heparin and dermatan sulfate interact with HCII and increase the rate of thrombin inhibition more than 1000-fold. HCII is homologous to antithrombin, which inhibits not only thrombin but also factors Xa and IXa when bound to heparan sulfate synthesized by endothelial cells; by this mechanism, antithrombin may prevent thrombosis of intact blood vessels. Mutations in the antithrombin gene that decrease its expression by half are associated with an increased risk of venous thromboembolism. 1 Despite much effort on the part of many investigators, a convincing association between HCII deficiency and venous or arterial thrombosis has not been established. 3 In animal studies, mice that completely lack HCII develop clots more rapidly in their carotid arteries after oxidative damage to the endothelium than do wild-type mice. 4 This work provides direct evidence that HCII can have antithrombotic activity in vivo and draws attention to the arterial system as a potential target of action of HCII. Two clinical studies 5,6 reported in Circulation suggest that HCII may help to protect people from in-stent restenosis or carotid artery atherosclerosis. See p 2761In the first study, 5 134 consecutive patients with symptomatic coronary artery disease were treated with placement of conventional non-coated stents, followed by aspirin and ticlopidine for 1 month. Angiograms obtained during the procedure and 6 months later were evaluated in a blinded fashion to determine the degree of in-stent restenosis. Plasma HCII and antithrombin activities were measured at the 6-month follow-up visit. The HCII levels in this patient population varied over a somewhat wider range (37% to 212% of the mean reference value) than has been previously observed. 3 The authors arbitrarily divided their patients into 3 groups: Those with HCII activities Ͻ80% (32 patients), Ն80% and Ͻ110% (66 patients), and Ն110% (36 patients). The 3 groups were similar in terms of age, cardiovascular risk factors, and clinical manifestations of coronary artery disease. Six months after stent placement, the percent decrease in lumen diameter was significantly less (Pϭ0.046) in the high-HCII group (18.7Ϯ24.3%) than in the low-(29.0Ϯ29.0%) and intermediate-HCII (30.3Ϯ24.8%) groups. In-stent restenosis, defined as Ն50% decrease in lumen diameter, occurred at rates of 6.7% in the high-HCII group, 18.5% in the intermediate-HCII group, and 30.0% in the low-HCII group; the difference between the high-and low-HCII groups was significant (Pϭ0.0039). In a multivariate analysis, in-stent restenosis was negatively correlated with HCII activity (Pϭ0.042) and positively correlated with diabetes mellitus (Pϭ0.041); other parameters, including gender, age, total cholesterol, high-density lipoprotein (HDL) c...

Intracellular retention of hepatic serpins caused by severe hyperlipidemia

“…Antithrombin plays an anti‐inflammatory role by promoting endothelial production of prostacyclins, inhibiting activation of leukocytes and endothelial cells directly and attenuating TNF‐α‐dependent responses (7). Additionally, heparin cofactor II (26) and the β‐form of antithrombin (27, 28) are relevant inhibitors of thrombin in the arterial wall, which is paramount to inhibit smooth muscle proliferation and macrophage migration in plaque formation. Thus, plasma deficiency of these serpins, caused by its intracellular accumulation, could also contribute to atherosclerosis.…”

Decreased heparin cofactor II activity is associated with impaired endothelial function determined by brachial ultrasonography and predicts cardiovascular events

“…The activity of thrombin in the vasculature is finely controlled and modulated by HCII and ATIII. HCII and ATIII both serve as physiological 0167 inhibitors of thrombin actions, and inhibit thrombin activity more than 1000-fold after binding to glycosaminoglycans [5,6]. HCII also has been proposed to modulate coagulation or to participate in processes such as inflammation, atherosclerosis, and even wound repair [7].…”

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

“…Plasma was stored at 80 until use. Plasma HC and AT activities were measured as previously described 28,29) .…”

“…Thus, there is a possibility that HC can attenuate the progression of atherosclerosis by inhibiting thrombin action at the injured peripheral arteries. We previously reported an elderly woman with congenital HC deficiency who manifested multiple atherosclerotic disorders 25) , and we have reported the results of clinical studies showing that HC can reduce in-stent restenosis after percutaneous coronary intervention and reduce plaque formation in the carotid artery [26][27][28] . Moreover, we and Tollefsen's group have reported that prominently accelerated vascular remodeling, including atherosclerosis, was observed in HC -deficient mice compared to HC wild-type mice 29,30) .…”