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PubMed1988

In vivo catabolism of heparin cofactor II and its complex with thrombin: evidence for a common receptor-mediated clearance pathway for three serine proteinase inhibitors.

The plasma clearance of 125I-labeled human heparin cofactor II and its complex with thrombin was studied in mice to determine whether a specific mechanism exists for the catabolism of the inhibitor-proteinase complex. Initial studies demonstrated that murine plasma contains a heparin cofactor II-like inhibitor as shown by the presence of a dermatan sulfate-sensitive thrombin inhibitor. Human heparin cofactor II cleared from the circulation of mice with an apparent half-life of 80 min while heparin cofactor II-thrombin complexes cleared with an apparent half-life of only 10 min. The specificity of the clearance mechanism was investigated by clearance competition studies involving coinjection of excess unlabeled heparin cofactor II-alpha-thrombin, antithrombin III-alpha-thrombin, or alpha 1-proteinase inhibitor-elastase, and by tissue distribution studies. The results demonstrated that the clearance of 125I-labeled heparin cofactor II-alpha-thrombin is a receptor-mediated process, and that the same hepatocyte receptor system recognizes complexes containing heparin cofactor II, antithrombin III, and alpha 1-proteinase inhibitor.

Animals↗
PubMed1990

Comparative studies of heparin cofactor activity toward antithrombin III and heparin cofactor II, and antithrombin III affinity between low molecular weight heparin and unfractionated heparin.

The accelerating effects of an UF heparin (Novo) and two LMW heparins (Fragmin and PK 10169) on AT III and HC II were investigated in a purified system. The effects of these heparins on APTTs were examined using human plasma. Fractionation of these heparins by affinity column chromatography yielded the following results: UF heparin was separated into two distinct fractions, LA and HA for AT III. Both LMW heparins were separated into three fractions: NA, LA, and HA for AT III. The accelerating effects of these fractions on both antithrombin and anti-Factor Xa activity of AT III were dependent on the strength of their affinity to AT III. The accelerating effects of these fractions on the antithrombin activity of HC II was independent of the strength of their affinity for AT III. LA had a much stronger anticoagulant activity of HC II toward thrombin than did HA. It is concluded that LA for AT III is necessary to show HC II activity.

Antithrombin III↗
PubMed1994

Thrombin-based antithrombin assays show overestimation of antithrombin III activity in patients on heparin therapy due to heparin cofactor II influence.

An extensive comparison has been performed on the clinical chemistry automate Hitachi 717 between thrombin- and Factor Xa-based methods for determination of antithrombin III activity. In 460 patients who did not receive any heparin therapy the agreement between assays was in general close although the thrombin-based methods resulted in slightly higher assignments of 0.3-2.6% antithrombin III activity. The discrepancy was, however, substantial in plasmas from patients receiving heparin of > or = 20000 IU/day, resulting in plasma levels of heparin of 0.8-1.2 IU/ml. Thus, analysis of 102 patients showed that the thrombin-based methods resulted in, on average, 7-16% higher assignment of antithrombin III activity as compared to the Factor Xa-based method used. Addition of antibodies to antithrombin III and heparin cofactor II revealed that the discrepancy was primarily due to contribution of heparin cofactor II activity in the thrombin-based methods. The results thus suggest that the Factor Xa-based antithrombin III activity method provides more valid results in patients on heparin therapy.

Antithrombin III↗
PubMed1992

Heparin cofactor II deficiency in the elderly: comparison with antithrombin III.

We investigated heparin cofactor II (HC II) levels and their relationship to other haemostatic factors in the elderly in comparison with antithrombin III (AT III). We measured plasma HC II activity levels in 166 subjects aged from 61 to 99 years using a chromogenic method. HC II levels (94.4 +/- 18.5%) in the healthy elderly subjects were significantly (p less than 0.001) lower than in 40 healthy adult controls under 60 years of age (mean age: 51.5 years; 111.6 +/- 21.2%). HC II levels in the elderly subjects decreased further with age (r = 0.308, p less than 0.001) and the extent of the decrease was more marked than that for AT III (r = 0.179, p less than 0.05). There was no significant sex difference in HC II levels in the elderly. HC II levels correlated significantly with AT III levels and with acute phase reactants including sialic acid, fibrinogen, and PAI-1. HC II levels also correlated with factor VII, plasminogen, alpha 2-plasmin inhibitor, serum lipid, pseudocholinesterase, and albumin levels. These correlations were also found for AT III except active PAI-1 and tPA-PAI-1 complexes, but the correlations with acute phase reactants were stronger for HC II than AT III. We divided 154 elderly subjects into 4 groups by their pseudocholinesterase and albumin levels to estimate the effect of nutritional status on antithrombin activity in the elderly. HC II levels were normal in the elderly subjects with a good nutritional state (103 +/- 18%), but were significantly decreased in those with malnutrition (85 +/- 15%, p less than 0.001). AT III levels also showed the same tendency. These results indicate a decrease in the reserve capacity to inhibit thrombin generation at sites of atherosclerosis in response to trigger events. The deficiency of two major antithrombin factors in the elderly may indicate a tendency to thrombosis, especially in individuals with malnutrition. When considering the clinical significance of HC II, several other parameters, including age, nutritional status, hepatic synthetic ability, and the presence or absence of acute phase reaction should also be assessed.

Acute-Phase Proteins↗
PubMed1999

[Heparin cofactor II, a thrombin inhibitor with a still not clarified physiologic role].

Heparin Cofactor II (HCII) is a glycoprotein in human plasma which inactivates thrombin rapidly in the presence of dermatan sulfate. Inhibition occurs by formation of a stable equimolar complex between HCII and thrombin. HCII association with thrombotic events has not always been observed, thus decreased HCII does not appear to be a strong risk factor for thromboembolic events. Reduced HCII levels have been detected in different clinical conditions, such as hepatic failure, disseminated intravascular coagulation, thalasemina, sickle cell anemia. Increased physiological levels have been found in pregnant women and oral contraception. In our laboratory, we measured HCII plasmatic levels in the normal Buenos Aires city population and in patients under different clinical conditions, such as sepsis, diabetis, burns, oral anticoagulation and in patients treated with heparin, hyperhomcysteinemia in whom septic and diabetic patients showed decreased values. HCII thrombin inhibition possibly takes place in extravascular sites where dermatan sulfate is present. HCII activity would be important in the regulation of wound healing, inflammation, or neuronal development.

Coagulation Protein Disorders↗
PubMed1987

Activation of heparin cofactor II by fibroblasts and vascular smooth muscle cells.

Inhibition of thrombin by heparin cofactor II (HCII) is accelerated by dermatan sulfate, heparan sulfate, and heparin. Purified HCII or defibrinated plasma was incubated with washed confluent cell monolayers, 125I-thrombin was added, and the rate of formation of covalent 125I-thrombin-inhibitor complexes was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Fibroblasts and porcine aortic smooth muscle cells accelerated inhibition of thrombin by HCII 2.3-7.5-fold but had no effect on other thrombin inhibitors in plasma. Human umbilical vein endothelial cells and mouse macrophage-derived cells did not accelerate the thrombin-HCII reaction. IMR-90 normal human fetal lung fibroblasts treated with heparinase or heparitinase accelerated the thrombin-HCII reaction to the same degree as untreated cells. In contrast, treatment with chondroitinase ABC almost totally abolished the ability of these cells to activate HCII while chondroitinase AC had little or no effect, suggesting that dermatan sulfate was responsible for the activity observed. [35S]Sulfate-labeled proteoglycans were isolated from IMR-90 fibroblast monolayers and conditioned medium and fractionated into two peaks on Sepharose CL-2B. The lower Mr proteoglycans contained 74-76% dermatan sulfate and were 11-25 times more active with HCII than the higher Mr proteoglycans which contained 68-97% heparan sulfate. The activity of the lower Mr proteoglycans decreased 70-90% by degradation of the dermatan sulfate component with chondroitinase ABC. These results confirm that dermatan sulfate proteoglycans are primarily responsible for activation of HCII by IMR-90 fibroblasts. We suggest that HCII may inhibit thrombin when plasma is exposed to vascular smooth muscle cells or fibroblasts.

Animals↗
PubMed1990

Heparin cofactor II levels are increased by the use of combined oral contraceptives.

Heparin cofactor II (HCII) was assayed by a microtitre amidolytic substrate technique. A linear response was obtained up to 1.5 U/ml and HCII levels were not affected by freezing and thawing the plasma. The assay was validated by comparing HCII and antithrombin III (AT III) levels in AT-III-deficient plasmas and samples from critically ill patients. Higher HCII levels were found in healthy normal women than in healthy normal men (means 1.16 and 0.97 U/ml, respectively, P less than 0.01). A significant increase in HCII levels from 0.86 to 1.10 U/ml (mean values) was seen in healthy normal women starting on combined oral contraceptive (COC) preparations (P less than 0.001). Increased HCII levels were maintained over a 6-month period, but fell towards normal 14 days after stopping COC, although they were still significantly higher than before starting COCs. The discrepancy in HCII level between normal men and women may be due to COC use. In clinical studies, different reference ranges should be used for men and women, and the need for careful questioning about the use of COCs is emphasized.

Adolescent↗
PubMed1987

Antithrombin III and heparin cofactor II in patients with chronic renal failure undergoing regular hemodialysis.

Heparin enhances the inhibition rate of thrombin by both antithrombin III (AT III) and heparin cofactor II (HC II). We studied the activity of these two plasma proteins in patients with chronic renal failure (CRF) undergoing regular hemodialysis as their heparin requirements varied widely. In 77 normal blood donors, normal ranges (mean +/- 2 SD) were 82-122% for AT III and 65-145% for HC II. When compared with these controls 82 dialyzed CRF patients had a subnormal AT III activity and a significantly (p less than 0.001) lower HC II activity. To evaluate the effect of hemodialysis we compared AT III, HC II and total proteins in plasma before and after dialysis in 24 patients (12 with normal and 12 with low basal HC II activity). AT III and HC II activities significantly (p less than 0.001) increased in absolute value. When related to total plasma proteins, in order to suppress the influence of hemoconcentration induced by dialysis, AT III decreased significantly (p less than 0.01) whereas HC II increased slightly but significantly (p less than 0.01) in the 12 patients with low initial HC II activity. The decrease of AT III induced by heparin administrated during dialysis is likely to account for this relative decrease of AT III activity. A modification of the distribution of both HC II and heparin between the vascular wall and the circulating blood is evoked to explain the relative increase in HC II activity and the need for higher heparin dosage in patients with low HC II levels.

Adult↗
PubMed1997

Mechanism of thrombin inhibition by heparin cofactor II in the presence of dermatan sulphates, native or oversulphated, and a heparin-like dextran derivative.

The kinetics of thrombin inhibition by heparin cofactor II (HC II) in the presence of dermatan sulphates, native (DS), or oversulphated (DSS 1 and DSS 2) and a biospecific dextran derivative substituted with carboxymethyl, carboxymethyl-benzylamide and carboxymethyl benzylamide-sulphonate functional groups (CMDBS), has been studied as a function of the sulphated polysaccharide concentration. The initial HC II and thrombin concentrations were set at equimolar levels. Analysis of the experimental data obtained for DS, DSS1 and DSS2 was performed using a previously described model which allows computation of the dissociation constant (KPS,HC) of the polysaccharide-HC II complex and the rate constant of thrombin inhibition by the polysaccharide-HC II complex (k). A KPS.HC of 9.6 x'10(-7) M and a k of 4.5 x 10(9) M-1 min-1 were found for DS, whereas KPS,HC 2.1 x 10(-6) M, k 1.1 x 10(10) M-1 min-1 and KPS,HC 4.3 x 10(-7) M, k 1.4 x 10(10) M-1 min-1 were found for DSS1 and DSS2, respectively. Knowing that DSS1 has a sulphur content per disaccharide of 7.8%, compared with 11.5% for DSS2, these results indicate that the polysaccharide affinity for HC II is increased only in the case of DSS 2, whereas the oversulphation increases the reactivities towards thrombin of both complexes DSS1-HC II and DSS2-HC II. A better conformation of these complexes may favour a faster interaction with the protease. Unlike heparin, DS at concentrations higher than 10(-5) M does not modify the reaction rate of thrombin inhibition, a fact which can be explained by the absence of complex formation between DS and thrombin. The experimental data obtained for CMDBS fit a kinetic model in which the biospecific dextran derivative rapidly forms a complex with thrombin which is more reactive towards HC II than the free protease. The reaction rate remained unchanged for CMDBS concentrations equal to or higher than 10(-5) M, whereas CMDBS was found to interfere strongly with the fibrinogen-thrombin interaction. These data suggest that CMDBS has a strong affinity for the protease and no affinity for HC II. The computed dissociation constant of the CMDBS-thrombin complex (KPS,E) was 2.4 x 10(-7) M and the rate constant of the reaction of this complex with HC II (k) was 1.7 x 10(8) M-1 min-1. These findings indicate that CMDBS exerts its catalytic effect through a unique mechanism of action and may constitute a new class of anticoagulant drugs.

Dermatan Sulfate↗
PubMed1990

Characteristics of the chemotactic activity of heparin cofactor II proteolysis products.

The physiological function of the serpin (serine proteinase inhibitor) heparin cofactor II (HCII) is not well understood. A role for HCII as an inhibitor of thrombin in the presence of dermatan sulfate and heparin has been proposed. Neutrophils (PMN) are the major cellular component of acute inflammation. HCII can be proteolytically inactivated by cathepsin G (CG) and elastase (LE), which are released by stimulated PMN. We have recently shown that reaction products of HCII with CG and LE are potent chemotaxins for PMN. Monocytes (monos) appear later in the course of inflammation than do PMN. They differentiate into macrophages in the tissues and participate in healing of damaged tissue and initiating immune responses. We found that the proteolysis products of HCII were chemotactic for monocytes in a fashion similar to their effects on PMN. At 10(-8) to 10(-9) M, the chemotactic activity of HCII proteolysis products was comparable to that of 10(-8) M N-formyl-Met-Leu-Phe (fMLP). The chemotactic activity of HCII-proteinase reaction products is mediated by a different mechanism than that of alpha 1 proteinase inhibitor (alpha 1 PI)-LE complexes or fMLP. Our data suggest that chemotactic activity generated by proteolysis of HCII is not due to the conformational change induced by cleavage of the exposed loop near the reactive site nor by release of the reactive site peptide. We also compared the effects of HCII reaction products and fMLP on expression of Mac-1 and p150,95 adhesive proteins. Mac-1 has been implicated in mono adhesion and chemotaxis and as a potential initiator of coagulation. The surface expression of Mac-1 was not increased above control levels by incubation of leukocytes with HCII digests, even though fMLP did increase surface Mac-1. Proteolysis products of HCII could play a role in the initial influx of PMN into a thrombus, and in the transition from acute to chronic inflammation, or to granulation and healing.

Antigens, Differentiation↗
PubMed1997

Arginine 200 of heparin cofactor II promotes intramolecular interactions of the acidic domain. Implication for thrombin inhibition.

Heparin cofactor II (HCII) is presumed to be a physiological inhibitor of the serine proteinase thrombin. The reaction between HCII and thrombin is quite unique, because it involves an unusual HCII-reactive site loop sequence of Leu444-Ser445, requires the presence of glycosaminoglycans for optimal activity and involves a protein-protein interaction besides the reactive site loop-active site interaction characteristic of serine proteinase inhibitor-serine proteinase pairs. Two mutations at a unique HCII residue, Arg200 --> Ala or Glu, were generated by site-directed mutagenesis. The mutations did not alter either HCII binding to heparin-Sepharose or HCII inhibition of thrombin in the presence of heparin or dermatan sulfate, suggesting that Arg200 is not part of the glycosaminoglycan binding site of HCII. In the absence of glycosaminoglycan, there was a significant increase in alpha-thrombin inhibition by the Arg200 mutants as compared with wild type recombinant HCII (wt-rHCII), whereas inhibition rates with chymotrypsin were identical. Inhibition of gammaT-thrombin, which lacks anion-binding exosite 1 ((ABE-1), the region of alpha-thrombin that interacts with the acidic domain of HCII), was significantly reduced compared with alpha-thrombin, but the reduction was more dramatic for the Arg200-rHCII mutants. Hirugen, which binds to ABE-1 of alpha-thrombin, also diminished inhibition of alpha-thrombin by the Arg200-rHCII mutants to nearly wt-rHCII levels. Both Arg200-rHCII mutants had significantly increased ka values as compared with wt-rHCII, whereas the kd rates were unchanged. Collectively, these results suggest that the improved inhibitory activity of the Arg200-rHCII mutants is mediated by enhanced interactions between the acidic domain and ABE-1, resulting in an increased HCII-thrombin association rate.

Arginine↗
PubMed2003

Evaluation of the haemostatic potential of factor VIII-heparin cofactor II hybrid proteins in a mouse model.

We constructed factor VIII-heparin cofactor II (FVIII-HCII) hybrid molecules, which are more readily activated by thrombin in vitro than the respective wild-type molecules. The hybrid proteins were tested in a murine model of haemophilia A to investigate their haemostatic efficacy in vivo. Bleeding characteristics, measured using standard tail-tip cutting techniques, were total blood loss, bleeding time and survival rate. FVIII-HCII hybrids were found to be effective in preventing bleeding in FVIII knockout mice. While in vitro experiments showed that the chimaeric molecules had higher haemostatic functions than the wild-type proteins, the variables analysed in vivo were similar for both proteins.

Animals↗
PubMed1992

Significance of high levels of heparin cofactor II in the plasma and urine of adult patients with nephrotic syndrome.

Heparin cofactor II (HCII) is a thrombin inhibitor in human plasma which displays similarities with antithrombin III (ATIII). Hereditary HCII deficiency was recently reported to be associated with thrombophilia. Since thromboembolism constitutes one of the main complications of the nephrotic syndrome (NS), both activities and antigen concentrations of HCII and ATIII were measured in the plasma and urine of 33 adult patients with nephrotic syndrome. The mean HCII plasma level was significantly increased whereas the ATIII level was decreased. Plasma HCII was significantly correlated with proteinuria and with the fibrinogen level, suggesting that HCII could act as an acute phase reactant in patients with NS. HCII antigen was detectable in 16 of the 24 available urine samples, whereas ATIII antigen was present in all of them. In addition, functionally active HCII was detected in most of the urine samples containing HCII antigen, while ATIII was only present in the inactive form. In conclusion, these findings suggest that HCII is submitted to a metabolic pathway different from that of ATIII in patients with NS.

Adolescent↗
PubMed2005

Placental dermatan sulfate: isolation, anticoagulant activity, and association with heparin cofactor II.

Pregnancy is associated with hemostatic challenges that may lead to thrombosis. Heparin cofactor II (HCII) is a glycosaminoglycan-dependent thrombin inhibitor present in both maternal and fetal plasma. HCII activity increases during pregnancy, and HCII levels are significantly decreased in women with severe pre-eclampsia. Dermatan sulfate (DS) specifically activates HCII and is abundant in the placenta, but the locations of DS and HCII in the placenta have not been determined. We present evidence that DS is the major anticoagulant glycosaminoglycan in the human placenta at term. DS isolated from human placenta contains disaccharides implicated in activation of HCII and has anticoagulant activity similar to that of mucosal DS. Immunohistochemical studies revealed that DS is associated with fetal blood vessels and stromal regions of placental villi but is notably absent from the syncytiotrophoblast cells in contact with the maternal circulation. HCII colocalizes with DS in the walls of fetal blood vessels and is also present in syncytiotrophoblast cells. Our data suggest that DS is in a position to activate HCII in the fetal blood vessels or in the stroma of placental villi after injury to the syncytiotrophoblast layer and thereby inhibit fibrin generation in the placenta.

Anticoagulants↗
PubMed1990

Non-enzymatic glycation reduces heparin cofactor II anti-thrombin activity.

The effects of non-enzymatic glycation on heparin cofactor II activity, at glucose concentrations which might be expected in physiological or diabetic conditions have been evaluated in this study. Radiolabelled glucose incorporation was associated with a loss of heparin cofactor anti-thrombin activity. The heparin cofactor heparin and dermatan sulfate-dependent inhibition of thrombin was significantly reduced, showing a remarkable decrease of the maximum second order rate constant. This study shows that heparin cofactor can be glycated at glucose concentrations found in the blood, and that this phenomenon produces a loss of heparin cofactor-antithrombin activity. These data suggest, furthermore, a possible link between heparin cofactor glycation and the pathogenesis of thrombosis in diabetes mellitus.

Antithrombins↗
PubMed1987

Heparin cofactor II: a simple assay method and results of its clinical application.

A simple assay method of heparin cofactor II (HC II) activity is described. The procedure is based on the following principle: Antithrombin III (AT III) in plasma is inactivated by addition of an IgG fraction of goat serum after immunization of the animals against human AT III. Complete inactivation of AT III could be shown by absence of an anti Xa-effect of heparinized plasma treated with this antibody. Thrombin was only partially inhibited after inactivation of AT III. The characteristics of this inhibition were typical for the action of HC II. This method was applied for an assay of HC II activity. After optimizing of the method practical application in clinical routine screening was carried out. A diminution of HC II was observed in liver cirrhosis and in DIC but not in AT III deficiency. In 15 out of 269 cases of recurrent DVT there were HC II activities below 70% of normal. In 4 out of these patients activities of HC II were repeatedly between 44% and 52%. In arterial obstructive disease there was an HC II activity of less than 60% in 18 out of 583 patients and in 11 of them the HC II levels were repeatedly between 45% and 54%.

Antithrombin III↗
PubMed1991

Heparin cofactor II deficiency in renal allograft recipients: no correlation with the development of thrombosis.

Heparin cofactor II (HC II) is a thrombin inhibitor in human plasma which displays great similarities with antithrombin III (AT III). Hereditary HC II deficiency was recently reported to be associated with thrombophilia. Since thromboembolism constitutes an important post-operative complication after renal transplantation, we measured HC II and AT III in the plasma of 118 healthy renal allograft recipients (RAR) and found stable low HC II and high AT III levels. Administration of azathioprine (AZA), cyclosporine A (CSA) or both as immunosuppressive therapy did not affect HC II levels, but CSA seems to have raised plasma AT III. The proportion of patients with HC II deficiency was significantly higher in RAR than the proportion we previously found (11) in healthy individuals (16.9% vs 1.5%). However, the proportions with low plasma HC II were not different in healthy RAR and in ten RAR with thrombotic events, suggesting that in transplanted patients, HC II deficiency is not in itself a risk factor for the development of thrombosis.

Adolescent↗