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PubMed1988

Naturally occurring human antibodies against two distinct functional domains in the heavy chain of FXI/FXIa.

We have isolated and probed the mechanism of action of two naturally occurring antibodies (Baltimore and Winston-Salem) against factor XI (FXI), that developed in patients congenitally deficient in FXI after replacement therapy. Purification on immobilized protein A and neutralization with monospecific antibodies against IgG heavy and light chain subtypes indicated that both antibodies were of restricted heterogeneity. Both Winston-Salem (IgG3 kappa) and Baltimore (IgG1 kappa) completely inhibited FXI coagulant activity at titers of 200 and 8 Bethesda units, respectively. Immunoaffinity columns prepared from each antibody were able to bind the heavy but not the light chain of reduced and alkylated activated FXI (FXIa). The activation of purified FXI by activated bovine factor XII (FXIIa), a reaction independent of high molecular weight kininogen (HK), was not inhibited by either antibody. The active site on the FXIa light chain was unaffected by either patient's IgG, as measured by its amidolytic activity. In contrast, one antibody (Baltimore) or its Fab' blocked the surface-mediated proteolytic activation of FXI by human FXIIa in a concentration-dependent fashion by preventing its binding to HK, but had no effect on the rate of activation of FIX by FXIa. In contrast, the other antibody (Winston-Salem) or its Fab' inhibited the activation of FIX by FXIa in a concentration-dependent fashion but did not inhibit binding of FXI to HK. We conclude that each of these two naturally occurring antibodies is directed against a specific, separate, and distinct epitope located in the heavy chain of FXIa, one near or at the domain essential for the activation of FIX by FXIa and the other close to the domain required for binding to HK.

Amides↗
PubMed2002

C1 inhibitor infusion modifies platelet activity in hereditary angioedema patients.

CONTEXT: C1 inhibitor (C1-INH) is an alpha2-globulin that blocks esterolytic activity of the first component of the classic complement cascade. The alpha-granules of normal human platelets also contain C1-INH, which is expressed on the platelet surface during platelet secretion in healthy patients, but it is clearly reduced in patients with hereditary angioedema (HAE). OBJECTIVE: To evaluate the effects of in vivo C1-INH concentrate infusion on platelet responsiveness and coagulation system activity in patients with HAE. DESIGN: Assessment of the platelet activity and plasma levels of C1-INH, activated factor XII (XIIa), and prothrombin fragment F1.2 (F1.2) before and after infusion of 15 U/kg of C1-INH concentrate. PATIENTS: In 6 patients (4 men and 2 women), HAE was diagnosed according to the accepted clinical and laboratory criteria. MEASUREMENTS: Platelet aggregation (final concentrations: adenosine diphosphate, 0.5, 1.25, and 2.5 microM; collagen, 5 microg/mL), C1-INH antigen (radial immunodiffusion), C1-INH activity (chromogenic substrates), and XIIa and F1.2 (enzyme-linked immunosorbent assay). RESULTS: After C1-INH infusion, we observed a prompt increase of C1-INH level and a slow return toward its plasma preinfusion values within 4 to 7 days, a significant decrease of both adenosine diphosphate- and collagen-induced platelet aggregation versus preinfusion values (maximum after 1-2 days; P <.001), and a rapid decrease of high basal values of XIIa and F1.2 in 30 and 120 minutes, respectively. CONCLUSIONS: These data show a role of C1-INH in the control of platelet activity and that its deficiency increases platelet aggregability and plasma levels of XIIa and F1.2 in patients with HAE.

Adenosine Diphosphate↗
PubMed2001

Bradykinin in the ascitic fluid of patients with liver cirrhosis.

Bradykinin, a nonapeptide with vasodilatory and permeabilizing activity, is generated through the cleavage of high-M(r) ('high-molecular-weight') kininogen by kallikrein, and its generation is facilitated by plasmin. In the ascitic fluid of patients with cirrhosis, there is massive cleavage of high-M(r) kininogen and activation of fibrinolysis, but bradykinin has never been measured directly. In the ascitic fluid of 24 patients with cirrhosis, we measured bradykinin-(1-9)-nonapeptide levels by RIA after liquid-phase and subsequent HPLC extraction, and those of its catabolic product bradykininin-(1-5)-pentapeptide by ELISA after liquid-phase extraction. Cleaved high-M(r) kininogen, activated factor XII and plasmin-antiplasmin complexes were measured in ascitic fluid and plasma. Plasma renin activity (PRA) was also determined. As a control, we also analysed plasma from 24 healthy subjects matched for sex and age with the patients. In the ascitic fluid from patients with cirrhosis, the median bradykinin-(1-9) concentration was 3.3 fmol/ml (range 0.2-29.0 fmol/ml), and the median bradykinin-(1-5) concentration was 210 fmol/ml (range 58-7825 fmol/ml). The levels of bradykinin-(1-5) in ascitic fluid were higher in patients with refractory ascites [median 1091 fmol/ml (range 58-7825 fmol/ml)] than in patients with responsive ascites [134 fmol/ml (72-1084 fmol/ml)] (P=0.010). Ascitic fluid levels of bradykinin-(1-9) were not related to the severity of ascites. PRA was higher in patients with refractory ascites [23.0 ng x h(-1) x ml(-1) (7.9-80.0 ng.h(-1).ml(-1))] than in patients with responsive ascites [6.9 ng x h(-1) x ml(-1) (0.9-29.4 ng x h(-1) x ml(-1))] (P=0.002). In ascitic fluid, 48% (19-68%) of high-M(r) kininogen was cleaved, and plasmin-antiplasmin complexes were more concentrated than in plasma (P=0.0001). In conclusion, in the ascitic fluid of patients with cirrhosis, both bradykinin-(1-9) and bradykinin-(1-5) are present, with cleavage of high-M(r) kininogen and activation of fibrinolysis. The highest levels of the long-lived metabolite bradykinin-(1-5) were found in the ascitic fluid of patients with refractory ascites and high PRA. Activation of the kinin system may therefore be involved in decompensating cirrhosis, but a cause-effect relationship remains to be established.

Adult↗
PubMed2001

The mRNAs of prekallikrein, factors XI and XII, and kininogen, components of the contact phase cascade are differentially expressed in multiple non-hepatic human tissues.

Recently RT-PCR studies had demonstrated the expression of plasma prekallikrein (PPK) mRNA in extrahepatic tissues. The questions arose whether that is illegitimate or regular expression, and whether the mRNAs of blood coagulation factors XI and XII, and high molecular weight kininogen, components of the contact activation cascade of blood coagulation are also expressed in non-hepatic tissues. These questions were addressed in the present study by employing quantitative RT-PCR. The relative mRNA levels of the respective proteins determined in 16 human tissues indicate legitimate extrahepatic transcription of at least three of the genes. Transcription of all genes was highest in the liver, but only PPK mRNA was detected in all 16 tissues, especially high levels in pancreas, kidney, testis, spleen and prostate. We conclude from these results that PPK is synthesized in significant amounts in non-hepatic tissues and that this locally synthesized PPK may have special local functions.

Blood Coagulation Factors↗
PubMed2000

Respiratory difficulty following bismuth subgallate aspiration.

Bismuth subgallate, an agent that initiates clotting via activation of factor XII, has been advocated for use in controlling bleeding during tonsillectomy and adenoidectomy. Direct aspiration of bismuth has produced pulmonary complications in laboratory animals, but no clinical correlation in humans has been previously described. We report 2 cases of bismuth aspiration that resulted in respiratory difficulty after tonsillectomy and adenoidectomy. Neither child's respiratory compromise required airway intubation. This report of pulmonary complications secondary to bismuth aspiration should alert surgeons to the potential for airway problems when using bismuth as a hemostatic agent for tonsillectomy and adenoidectomy.

Adenoidectomy↗
PubMed1999

Blood compatibility of surfaces with immobilized albumin-heparin conjugate and effect of endothelial cell seeding on platelet adhesion.

Endothelial cell (EC) seeding significantly improves the blood compatibility of artificial surfaces. Although a coating consisting of albumin and heparin (alb-hep) is a suitable substrate for seeded ECs, binding of ECs to the substrate further improves when small amounts of fibronectin are present in the alb-hep coating. Alb-hep conjugate was immobilized on carbon dioxide gas plasma-treated polystyrene (PS-CO(2)), thereby significantly increasing the recalcification time of blood plasma exposed to this surface. Furthermore, surface-immobilized alb-hep conjugate inhibited exogenous thrombin. Heparin activity was reduced by adding fibronectin on top of a monolayer of alb-hep conjugate, but not by simultaneous coating of fibronectin and alb-hep conjugate. Coating of PS-CO(2) with alb-hep conjugate significantly decreased contact activation (FXII activation). The number of platelets deposited from blood plasma on PS-CO(2) coated with alb-hep conjugate was twice as high as on PS-CO(2) coated with albumin. Addition of fibronectin to alb-hep conjugate-coated PS-CO(2) had no significant effect on the number of adhered platelets. Seeding of the substrates with ECs significantly reduced the number of adhered platelets under stationary conditions. Platelets deposited onto endothelialized surfaces were primarily found on endothelial cell edges, and sparingly on areas between ECs. In conclusion, alb-hep conjugate-coated surfaces display anticoagulant activity. ECs adhering to and proliferating on this coating significantly decrease the number of platelets which adhere to the surface. Therefore, alb-hep conjugate-coated surfaces form a suitable substrate for seeding of ECs in low density. Although application of fibronectin on top of the coating decreases the anticoagulant activity to some extent, it might be useful in view of the improved adherence of ECs to the coating.

Animals↗
PubMed1993

Protein adsorption onto poly(ether urethane ureas) containing Methacrol 2138F: a surface-active amphiphilic additive.

Surface characterization and protein adsorption studies were carried out on a series of additive dispersed and additive coated poly(ether urethane ureas), PEUUs, to characterize early events in the blood compatibility of these materials. A hypothesis that is based on surface hydrophilicity, surface flexibility, and adsorption media has been developed to understand the modulated adsorption of plasma proteins by PEUU additives. Electron spectroscopy for chemical analysis (ESCA) and contact angle analysis were performed on two PEUU formulation as well as on PEUU formulations modified with Methacrol 2138F (co[diisopropylaminoethyl methacrylate (DIPAM)/decyl methacrylate (DM)][3/1]) or acrylate or methacrylate polymer or copolymer analogs of Methacrol 2138F. Methacrol 2138F is a commercially used amphiphilic copolymethacrylate. ESCA showed that the PEUUs loaded with Methacrol 2138F or with its hydrophilic component, homopoly (DIPAM) (h-(DIPAM)), had a higher percentage of nitrogen at their surfaces than did the base PEUUs. Contact angle analysis also showed that the air side of PEUU formulations loaded with Methacrol 2138F were more hydrophobic than was the air side of base PEUUs when films were cast from dimethylacetamide. However, during contact angle testing, the air side of PEUU films loaded with Methacrol 2138F rapidly became more hydrophilic than did the air side of the base PEUU films. A radioimmunoassay and whole or diluted human plasma were also used to characterize the presence of the proteins fibrinogen, immunoglobulin G, factor VIII/von Willebrand factor, Hageman factor (factor XII), and albumin, on the surface of the same PEUUs as analyzed by ESCA and contact angle. The protein adsorption assay showed that PEUU films loaded or coated with Methacrol 2138F, with a copolyacrylate analog of Methacrol 2138F (co(diisopropylaminoethyl acrylate [DIPAA]/decyl acrylate [DA]) [3/1]), or with the hydrophilic polyacrylate or polymethacrylate component analogs of Methacrol 2138F (h-DIPAM or h-DIPAA) adsorbed significantly lower amounts of the proteins than did either the base PEUU formulations or the homopoly(decyl methacrylate) (h-DM) or homopoly(decyl acrylate) (h-DA) coated or loaded PEUUs.

Adsorption↗
PubMed1993

Protein adsorption to poly(ether urethane ureas) modified with acrylate and methacrylate polymer and copolymer additives.

To understand better blood interactions with poly(ether urethane urea) (PEUU) materials, a radioimmunoassay and whole or diluted human plasma were used to characterize the presence of fibrinogen, immunoglobulin G, factor VIII/von Willebrand factor, Hageman factor (factor XII), and albumin on a PEUU formulation and on PEUU formulations modified with the amphiphilic additive Methacrol 2138F (co[diisopropylaminoethyl methacrylate (DIPAM)/decyl methacrylate] [3/1]), or with hydrophobic acrylate or methacrylate polymer or copolymer additives. The protein adsorption assay showed that PEUU films loaded or coated with Methacrol 2138F (Methacrol) or homopoly-DIPAM (h-DIPAM) adsorbed significantly lower amounts of the studied proteins than did either the base PEUU formulations or the PEUUs loaded with the more hydrophobic acrylate or methacrylate polymer additives. Experiments with Methacrol-loaded PEUUs, where the loading of Methacrol was varied from 0.25 wt% to 20.0 wt%, showed that the adsorption of each of the characterized proteins did not vary significantly throughout the Methacrol loading range, and that all Methacrol-loaded PEUU formulations adsorbed significantly lower amounts of the studied proteins than did the unloaded PEUU. Phase separation within the additive loaded PEUUs was characterized by scanning electron microscopy (SEM). The solubility parameters of the additives, as well as of the base PEUU, were calculated and used to interpret differences in phase separation of the additive modified PEUUs. The analysis showed that additives of lower solubility parameter phase-separated into fewer large microdroplets within the PEUU matrix. SEM analysis also showed that additive microdroplets were not present on the air side surface of loaded PEUUs. To explain the differences in protein adsorption to the air side of additive loaded PEUUs when compared to the base PEUU, it was assumed that the additives near this region of the solvent swollen PEUU matrix may have migrated to, at, or near the PEUU-air interface during film formation, creating an additive enriched PEUU surface region. Once at this surface region, it was suggested that dynamic surface reorientation in response to an aqueous medium ensured that the additives were able significantly to influence protein adsorption behavior only if they interacted with aqueous media more favorably than the PEUU.

Acrylates↗
PubMed1994

In vitro plasma protein adsorption and kallikrein formation on 3-mercaptopropionic acid, L-cysteine and glutathione immobilized onto gold.

3-Mercaptopropionic acid (MPA), L-cysteine (L-cys), and glutathione (GSH) monolayers were immobilized onto gold and used in in vitro protein tests. The surfaces were characterized with ellipsometry, static contact angle measurements, atomic force microscopy, and Fourier transform infrared reflection absorption spectroscopy (FT-IRAS). After incubations in human plasma and antibody solutions, the surface antisera binding patterns were determined with ellipsometry. Using serum instead of plasma, complement activation was studied in the same fashion. Activated coagulation Factor XII and kallikrein formation on the surfaces and in the plasma were studied using a kallikrein-specific colorimetric assay. 3-Mercaptopropionic acid indicated contact activation of coagulation but L-cysteine did not. Glutathione displayed low deposition of plasma proteins, large deposition of proteins from serum, and did not promote kallikrein formation. None of the surfaces could be attributed complement activating properties, as determined by antibody deposition. The present study demonstrates that surface biology in complex model systems can be conveniently studied in vitro through systematic and well defined surface modifications.

3-Mercaptopropionic Acid↗
PubMed1995

Control of contact activation on end-point immobilized heparin: the role of antithrombin and the specific antithrombin-binding sequence.

The uptake and activation of FXII from blood plasma was studied in small-diameter polyethylene tubing, surface-modified by end-point immobilization of heparin. Two preparations of heparin were used to modify the contact-activating properties of the plastic tubing: unfractionated, functionally active heparin and low-affinity heparin, lacking the specific antithrombin-binding sequence and virtually devoid of anticoagulant activity. The uptakes of FXII on the two heparin surfaces were similar. No activated FXII could be demonstrated on the unfractionated heparin surface, whereas on the low-affinity heparin surface nearly all FXII underwent spontaneous activation. The suppression of FXII activation on the unfractionated heparin surface was investigated by using plasma depleted of antithrombin, complement C1 esterase inhibitor, or both. The removal of antithrombin resulted in extensive activation of FXII, whereas the depletion of C1 esterase inhibitor had only a minor effect. Experiments with recalcified plasma showed rapid clot formation during exposure to the low-affinity heparin surface. After depletion of antithrombin, but not complement C1 esterase inhibitor, the recalcified plasma clotted in contact with the unfractionated heparin surface as well. We conclude that antithrombin and the antithrombin-binding sequence in the surface-immobilized heparin are essential for the prevention of surface activation of FXII and triggering of the intrinsic coagulation system.

Animals↗
PubMed2004

Scaled interfacial activity of proteins at the liquid-vapor interface.

A principal conclusion drawn from observations of time- and concentration-dependent liquid-vapor (LV) interfacial tension gamma(lv) of a diverse selection of proteins ranging from albumin to ubiquitin spanning nearly three decades in molecular weight (MW) is that concentration scaling substantially alters perception of protein interfacial activity as measured by reduction in gamma(lv). Proteins appear more similar than dissimilar on a weight/volume basis, whereas molarity scaling reveals a "Traube-rule" ordering by MW, suggesting that adsorption is substantially driven by solution concentration rather than diversity in protein amphilicity. Scaling as a ratio-to-physiological-concentration demonstrates that certain proteins exhibit the full possible range of interfacial activity at and well-below physiological concentration, whereas others are only weakly surface active within this range, requiring substantially higher solution concentration to achieve reduction in gamma(lv). Important among this latter category of proteins are the blood factors XII and XIIa, assumed by the classical biochemical mechanism of plasma coagulation to adsorb to procoagulant surfaces, even in the presence of overwhelming concentrations of other blood constituents such as albumin and immunoglobulin that are shown by this work to be among the class of highly surface-active proteins at physiologic concentration. A comparison of pendant drop and Wilhelmy balance tensiometry as tools for assessing protein interfacial activity shows that measurement conditions employed in the typical Wilhelmy plate approach fails to achieve the steady-state adsorption condition that is accessible to pendant drop tensiometry.

Adsorption↗
PubMed2005

Scaled interfacial activity of proteins at a hydrophobic solid/aqueous-buffer interface.

Contact-angle goniometry confirms that interfacial energetics of protein adsorption to the hydrophobic solid/aqueous-buffer (solid-liquid, SL) surface is not fundamentally different than adsorption to the aqueous-buffer/air (liquid-vapor, LV) interface measured by pendant-drop tensiometry. Adsorption isotherms of 9 globular blood proteins with molecular weight (MW) spanning from 10 to 1000 kDa on methyl-terminated self-assembled monolayer surfaces demonstrate that (i) proteins are weak surfactants, reducing contact angles by no more than about 15 degrees at maximum solution concentrations ( approximately 10 mg/mL); (ii) the corresponding dynamic range of spreading pressure Pi(a) < 20 mN/m; and (iii) the maximum spreading pressure Pi(max) (a) for these diverse proteins falls within a relatively narrow 5 mN/m band. As with adsorption to the LV interface, we find that concentration scaling substantially alters perception of protein interfacial activity measured by Pi(a). Proteins appear more similar than dissimilar on a weight/volume basis whereas molarity scaling reveals a systematic ordering by MW, suggesting that adsorption is substantially driven by solution concentration rather than diversity in protein amphilicity. Scaling as a ratio-to-physiological-concentration demonstrates that certain proteins exhibit Pi(max)(a) at-and-well-below physiological concentration whereas others require substantially higher solution concentration to attain Pi(max)(a). Important among this latter category of proteins is blood factor XII, assumed by the classical biochemical mechanism of plasma coagulation to be highly surface active, even in the presence of overwhelming concentrations of other blood constituents such as albumin and immunoglobulin that are shown by this work to be among the class of highly surface-active proteins at physiologic concentration. The overarching interpretation of this work is that water plays a dominant, controlling role in the adsorption of globular-blood proteins to hydrophobic surfaces and that energetics of hydration control the amount of protein adsorbed to poorly water-wettable biomaterials.

Adsorption↗
PubMed2005

Immunodepletion of albumin for two-dimensional gel detection of new mouse acute-phase protein and other plasma proteins.

Immunodepletion of albumin to improve the 2-D gel resolution of human plasma proteins has recently been described. With the importance of mouse models in many studies in which serum or plasma is often analyzed, we have adopted this approach to immunoprecipitate mouse albumin and evaluated its effectiveness for 2-D separation of mouse plasma proteins. Purified polyclonal antibodies against mouse albumin were effective depleting intact albumin as well as its numerous fragments from mouse plasma samples. Removal of albumin resulted in better resolution of mouse plasma proteins. Three proteins, alpha2-macroglobulin, coagulation factor XII, and hemopexin, that were previously either undetectable or poorly resolved, were identified from albumin-depleted 2-D gels by peptide mass fingerprinting. Albumin depletion also led to partial loss of several other proteins such as clusterin and gelsolin. This loss can be attributed to the interaction with albumin itself because the specificity of the antibody was demonstrated by Western blot. When applying this method to the 2-D separation of plasma from inflamed mouse induced by cutaneous burn injury with superimposed Pseudomonas aeruginosa infection, the upregulation of inter alpha-trypsin inhibitor heavy chain 4 (ITIH4) and hemopexin was unambiguously detected along with other mouse acute-phase proteins (APP), including haptoglobin and serum amyloid A. Based on the significant increase of ITIH4, we propose that this protein is a new member of mouse APP that are upregulated during the inflammatory response.

Acute-Phase Proteins↗
PubMed1993

Chymotrypsin inhibitory activity of normal C1-inhibitor and a P1 Arg to His mutant: evidence for the presence of overlapping reactive centers.

C1-inhibitor is a serine proteinase inhibitor that is active against C1s, C1r, kallikrein, and factor XII. Recently, it has been shown that it also has inhibitory activity against chymotrypsin. We have investigated this activity of normal human C1-inhibitor, normal rabbit C1-inhibitor, and P1 Arg to His mutant human C1-inhibitors and find that all are able to inhibit chymotrypsin and form stable sodium dodecyl sulfate-resistant complexes. The Kass values show that the P1 His mutant is a slightly better inhibitor of chymotrypsin than normal human C1-inhibitor (3.4 x 10(4) compared with 7.3 x 10(3)). The carboxy-terminal peptide of normal human C1-inhibitor, derived from the dissociated protease-inhibitor complex, shows cleavage between the P2 and P1 residues. Therefore, as with alpha 2-antiplasmin, C1-inhibitor possesses two overlapping P1 residues, one for chymotrypsin and the other for Arg-specific proteinases. In contrast, with the P1 His mutant, the peptide generated from the dissociation of its complex with chymotrypsin demonstrated cleavage between the P1 and P'1 residues. Therefore, unlike alpha 2-antiplasmin, chymotrypsin utilizes the P2 residue as its reactive site in normal C1-inhibitor but utilizes the P1 residue as its reactive site in the P1 His mutant protein. This suggests that the reactive center loop allows a degree of induced fit and therefore must be relatively flexible.

Amino Acid Sequence↗
PubMed1994

Generation of [Ala1,Thr6]bradykinin in the plasma of a snake, the reticulated python.

Incubation of heat-denatured plasma from the reticulated python, Python reticulatus with trypsin generated bradykinin-like immunoreactivity which was detected by radioimmunoassay using an antiserum raised against mammalian bradykinin. The primary structure of python bradykinin was established as Ala-Pro-Pro-Gly-Phe-Thr-Pro-Phe-Arg. This amino acid sequence contains two substitutions (Arg1-->Ala and Ser6-->Thr) compared with mammalian bradykinin. Treatment of python plasma with glass beads under conditions previously shown to generate [Thr6]bradykinin in the plasma of a turtle and an alligator did not generate bradykinin-like immunoreactivity. The data indicate that the plasma of a lepidosaur contains a kininogen but, unlike the plasma of chelonians and crocodilians, does not contain a prekallikrein activator related to Factor XII.

Amino Acid Sequence↗