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PubMed1992

Functional characterization of a variant factor XII (F XII Locarno) in a cross reacting material positive F XII deficient plasma.

The plasma of a healthy woman was found to contain half normal factor XII (FXII) antigen level (0.46 U/ml) without any FXII clotting activity (less than 0.01 U/ml). The variant FXII in this plasma, denoted as FXII Locarno, was partially characterized by immunological and functional studies on the proposita's plasma. FXII Locarno is a single chain molecule with the same size (Mr = 80 kDa) as normal FXII. Isoelectric focusing suggested an excess of negative charge in the variant FXII as compared to normal FXII. In contrast to FXII in normal plasma, FXII Locarno was not proteolytically cleaved upon prolonged incubation of proposita's plasma with dextran sulfate. Adsorption to kaolin was similar for both, abnormal and normal FXII. Incubation of the proposita's plasma with dextran sulfate and exogenous plasma kallikrein showed normal cleavage of FXII Locarno outside of the tentative disulfide loop Cys340-Cys467, but only partial cleavage within this disulfide loop. Furthermore, plasma kallikrein-cleaved abnormal FXII showed neither amidolytic activity nor proteolytic activity against factor XI and plasma prekallikrein. These results suggest a structural alteration of FXII Locarno, affecting the plasma kallikrein cleavage site Arg353-Val354 and thus formation of activated FXII (alpha-FXIIa).

Amides↗
PubMed2005

Collaborative study to establish a new biological reference preparation for prekallikrein activator.

An International Collaborative Study was organized to replace the current World Health Organization (WHO) International Standard (IS) for Prekallikrein Activator (PKA) and to establish a European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation (BRP). The project was jointly organized by the European Directorate for the Quality of Medicines (EDQM) and the National Institute for Biological Standards and Control (NIBSC) to identify and calibrate suitable materials that could act as an IS and a Ph. Eur. BRP. The current IS for PKA (82/530) is popular and stocks are declining rapidly, therefore necessitating calibration of a replacement. A Ph. Eur. BRP is needed, as PKA control on the finished product is part of the Official Control Authority Batch Release (OCABR) of Human Albumin. The current IS, 82/530 is a 5 per cent albumin solution spiked with purified PKA. However, during planning stages it was decided that the replacement IS (and BRP) should be made from a 20 per cent albumin preparation containing a significant level of PKA as the current IS is used to measure PKA in albumin and high levels are more likely to be encountered in more concentrated 20 per cent solutions. A suitable material was sourced by the EDQM and filled into ampoules at NIBSC and vials by the EDQM. Both preparations were included in the collaborative study that involved 31 laboratories from 17 countries. Another important goal of this study was to investigate the influence of the prekallikrein substrate (PKS) on PKA determination in albumin solutions following earlier concerns that variability amongst PKS prepared in-house could significantly affect PKA determinations. Laboratories were requested to perform their routine assays following Ph. Eur. guidelines and recommendations on doses, replication and randomization were also provided to study participants. Participants were requested to use material A (the current IS, 82/530) to perform at least 4 assays to determine PKA levels in sample B (NIBSC ampouled material, candidate IS, 02/168), sample C (EDQM material in vials candidate Ph. Eur. BRP Batch 1), and sample D (an ampouled preparation of 2.5 per cent albumin containing a lower level of PKA). A commercial substrate was provided for participants to perform half the assays and the remaining assays were to be performed using the laboratories' in-house substrate (where available). Collation of participants' results showed that samples B and C had the same level of PKA of 29 IU/ampoule, the concentration anticipated from development studies. Importantly, there was no significant difference between the PKA level obtained using the commercial substrate provided and the laboratories' own in-house substrate. Previous observations on lyophilized preparations of PKA indicate that the enzyme is very stable. Detailed investigations conducted in this study show that the PKA in albumin used to make samples B and C is very stable and suitable for long-term storage as a reference material.

Factor XIIa↗
PubMed1991

Modification of the influence of biomaterials on contact activation.

Knowledge of the influence of biomaterials on the contact phase activation of blood is important. Consequently, it is important to examine if the biomaterial influence is modified by the action of anticoagulants. Contact activation was determined by measuring FXII activity (FXIIA) by a chromogenic substrate assay. Cuprophan in the absence of anticoagulants and in the presence of heparin, low molecular weight heparin (LMWH) and hirudin was compared with controls. The controls were a polystyrene incubation test cell (PS) and two polyamide membranes, NR (zeta potential -28.6 mv and NRZ (zeta potential--18.0 mv). The investigation has confirmed that measurement of FXIIA is material dependent and demonstrated that contact activation can be mediated by antithrombotic agent.

Anticoagulants↗
PubMed1965

Activated human Hageman factor (XII).

An improved method for the isolation of highly purified active human Hageman factor has been described. An overall recovery of 25% with a purification of 10(6) has been achieved. Certain of the physical and chemical characteristics of XII have been elucidated. Selective chemical modification of functional groups and a variety of enzymatic assays have been employed in an effort to shed light on the mechanism of action of this procoagulant.

Amino Acids↗
PubMed2006

Impact of manufacturing improvements on clinical safety of albumin: Australian pharmacovigilance data for 1988-2005.

OBJECTIVE: To evaluate the impact of manufacturing improvements on the clinical safety of human albumin solutions in Australia. METHODS: This retrospective study examined the incidence of spontaneously reported post-market adverse drug reactions (ADRs) in Australia associated with successive generations of albumin products manufactured by the Bioplasma Division of CSL Limited (CSL Bioplasma) over 18 years (1988-2005). Key characteristics of each product generation which could affect clinical safety, such as purity, aggregates and prekallikrein activator (PKA) levels, were also identified from CSL batch release records. RESULTS: A total of 3.7 million bottles of iso-oncotic and hyperoncotic albumin products were distributed in Australia over the period. Improvements to manufacturing processes resulted in products with increased albumin purity, lower levels of impurities such as aggregates and PKA, and reduced batch-to-batch variation. The total ADR incidence (number of ADRs per 100 000 bottles distributed) associated with the products currently supplied was 1.5 and 1.7 for Albumex 4 (2VI) and Albumex 20 (2VI), respectively. This was a significant reduction compared with the earlier generation products Stable Plasma Protein Solution (14.1) and 20% Normal Serum Albumin (11.5), respectively (P<0.0001). In particular, hypotensive reactions declined substantially. CONCLUSION: Post-market pharmacovigilance data collected for successive generations of human albumin products supplied in Australia over 18 years indicates that manufacturing improvements have significantly improved the clinical safety profile of this product.

Albumins↗
PubMed1991

Effect of heparin on the activation of factor XII and the contact system in plasma.

We examined in purified systems and in human plasma whether heparin serves as a contact system activating compound. Purified human factor XII zymogen was not activated by heparin through an autoactivation mechanism, but was activated in the presence of purified prekallikrein. Zn2+ (12 microM) did not support autoactivation by heparin. The activation of factor XII and the contact system by heparin in plasma anticoagulated with citrate or with hirudin (not chelating ions) was examined by the cleavage of 125I-labeled factor XII and high molecular weight kininogen (HK). Heparin at 1.6 and 16 USP U/ml was not able to produce activation, in contrast to dextran sulfate (20 micrograms/ml) which supported activation of both factor XII and HK. This study indicates that heparinized plasma does not support activation of the contact system mediated through activation of factor XII. It is not expected that heparin anticoagulant therapy will contribute to activation of the contact system.

Complement C1 Inactivator Proteins↗
PubMed1990

[Evaluation of prekallikrein activator (PKA) activity in plasma-derived preparations].

The study was carried out on 111 series of human immunoglobulin preparations (81 series for intravenous use, 30 series for intramuscular use) produced abroad and in Poland. Kallikrein (KK) and prekallikrein activator (PKA) activities were identified using chromogenic substrate. S-2302 and proteinase inhibitors were tested by double immunodiffusion method. Several biochemical, biological and serological methods were also applied which are valid in the control of intravenous and intramuscular immunoglobulin preparations. It was found that trace amounts of PKA and KK are present in human immunoglobulin preparations for intravenous use such as Bioglobulina and Gamma-Venina (PKA 0.0092-0.0505 mu kat/L, and KK 0,-0.0093 mu kat/L). On the other hand normal human immunoglobulin preparations for intramuscular use had somewhat higher level of KK and PKA and anti-HBs Immunoglobulin preparations (5.50 mu kat/L and 153.91 mu kat/L) and Tetabulina preparations had very high levels of these factors as compared to remaining preparations (4.50 mu kat/L and 316.5 mu kat/L).

Europe↗
PubMed1986

The effect of pentosan polysulphate (SP54) on the human fibrinolytic system.

In human volunteers the oral and subcutaneous (s.c.) administration of SP54 enhanced the fibrinolytic potential of plasma. When the effect was compared between exercise and s.c. administration of SP54 the latter was found to "peak" at about 3 hours and to have a more sustained effect than the exercise. Oral versus s.c. administration suggests that only about 10% of the SP54 reaches the circulation by the oral route. However, repeat SP54 oral dosage did not elicit any resistance to the daily response over a period of five days and suggests that the volunteers used in this study tolerated repeated use of the drug with no ill-effects. The source of the fibrinolytic enhancement is as yet not fully explained and a hypothesis is presented which suggests that very small elevations of t-PA in plasma can affect the fibrinolytic potential in the presence of forming fibrin but may remain undetected by conventional immunometric assays.

Adult↗
PubMed1988

Determination of kallikreinogen (KKN) in human plasma by activation with Hageman factor fragment (F XIIf).

On the basis of activation of KKN by F XIIf an assay for determination of KKN levels was developed. The esterolytic activity of the activation product PK was measured with BAEE as substrate. After maximal activation of normal human plasma the esterolytic activity amounts to 16.82 +/- 2.03 mukat/l plasma (n = 25). The within run precision and day to day precision characterized by the variation coefficient were 2.5 and 4.9, respectively.

Arginine↗
PubMed1989

Monoclonal antibody to human high-molecular-weight kininogen recognizes its prekallikrein binding site and inhibits its coagulant activity.

We developed a mouse monoclonal antibody (MoAb 115-21) to human high-molecular-weight kininogen (HK) that recognizes its prekallikrein binding site (residues 565 through 595 of HK). The corresponding synthesized 31-amino acid peptide (peptide IV) was recently shown to retain native HK's prekallikrein binding property. The same peptide bound factor XI also, although less avidly. Our MoAb recognizes purified HK, peptide IV, and the light chain moiety of HK (where the peptide IV resides), as shown by enzyme-linked immunosorbent assay (ELISA) and Western blotting experiments. The apparent dissociation constant for the HK and MoAb 115-21 interaction was 2.2 nmol/L. It does not recognize low-molecular-weight kininogen (LK) with which HK shares its heavy chain moiety or any antigens in human plasma congenitally deficient in kininogens. The binding of MoAb 115-21 to purified light chain of HK was competitively inhibited by peptide IV. In addition, the antibody inhibits HK-dependent clotting activity of normal human plasma and dextran sulfate-mediated activation of prekallikrein in plasma and retards cleavage of HK in normal plasma after contact activation with dextran sulfate. Also, purified Fab fragments of MoAb 115-21 inhibited the HK-dependent coagulant activity and dextran sulfate-mediated prekallikrein activation in normal plasma. Since the kd for HK-MoAb 115-21 interaction is ten times lower than that of HK-prekallikrein, our data suggest that binding of MoAb 115-21 to HK's peptide IV site increases the free prekallikrein concentration in plasma and thus results in the decreased efficiency of factor XIIa-mediated activation of prekallikrein. Decreased levels of kallikrein thus formed may be responsible for the inhibition of HK-dependent clotting activity and the decrease in rate and extent of HK cleavage in normal plasma on contact activation with dextran sulfate. MoAb 115-21 may thus prove very useful, especially with its high affinity for HK, in further delineation of the role of HK and prekallikrein in contact activation and kinin-related human pathology.

Amino Acid Sequence↗
PubMed1988

[The so-called "contact" system of plasma: consequences of the activation of the Hageman factor].

The contact system of plasma includes 4 zymogens, Hageman factor, pre-kallikrein, factor XI and plasminogen, and a cofactor, the high molecular weight kininogen (HMWK). The activation of the contact system leads to the production of bradykinin, blood coagulation, fibrinolysis, complement activation and neutrophil stimulation. Consequently these phenomena generate a lot of pro-inflammatory factors which contribute to the local and systemic inflammatory processes.

Animals↗
PubMed1979

In vitro assay for prekallikrein activator (PKA).

The assay measures the action of prekallikrein in generating kallikrein. The prekallikrein activator is the limiting reagent. The product kallikrein is an esterase which can be quantitated using benzoyl arginine ethyl ester. The assay is reproducible and results are comparable with other methods. The large scale preparation of prekallikrein is described.

Blood Proteins↗
PubMed1979

The assay of prekallikrein activator in human blood products.

An assay for the determination of prekallikrein activator (PKA) in human blood products is described. Kallikrein released from a prekallikrein substrate preparation by PKA in the sample is determined using the synthetic substrate S-2302 (H-D-Pro-Phe-Arg-pNA). The PKA content of the sample is quantitated by interpolation from a standard line obtained using a reference preparation of plasma protein fraction (PPF). Endogenous kallikrein is estimated and an adjustment made for its contribution to the apparent PKA content of the sample. The results of determinations on a number of PPF, immunoglobulin and coagulation factor preparations are presented and discussed.

Blood Proteins↗
PubMed1986

The effect of C1 inhibitor upon Hageman factor autoactivation.

Using components purified from human plasma, we have examined the effects of C1 inhibitor (C1 INH), the primary inhibitor of activated Hageman Factor (HFa) and Hageman factor fragment (HFf), on Hageman Factor (HF) autoactivation. When Hageman factor was exposed to a negatively charged surface, provided by either a glass cuvette or dextran sulfate, the addition of C1 INH gave a dose-dependent inhibition of the activity observed. The ability of C1 INH to decrease the maximal enzymatic activity generated was markedly temperature dependent with inhibition increasing as the temperature was raised from 4 degrees C to 37 degrees C. Although the rates of both autoactivation and inhibition were decreased at lower temperatures (4 degrees C), the latter rate was more sensitive to temperature modulation. When HF (final concentration 1 mumol/L) was incubated with C1 INH (0.54, 1.07, and 2.14 mumol/L) in the absence of an initiating surface, no increases in enzymatic activity were observed for up to 48 hours regardless of the C1 INH concentration. However, SDS polyacrylamide gel electrophoresis of the incubation mixture revealed that HF autodigestion had occurred by 48 hours despite the presence of C1 INH. In addition, the appearance of a new band suggested that a complex had been formed between the inhibitor and activated HF. Our findings indicate that C1 INH does not prevent HF autoactivation but rather inactivates the products of HF autodigestion.

Complement C1 Inactivator Proteins↗
PubMed1985

Effect of cleavage of the heavy chain of human plasma kallikrein on its functional properties.

Human plasma kallikrein consists of an N-terminal heavy chain of molecular weight (mol wt) 52,000, linked by disulfide bonds to two light chain variants (mol wt 36,000 or 33,000). Although the active catalytic site of kallikrein resides on the C-terminal light chain, the role of the N-terminal heavy chain is less clear. We therefore studied an enzyme designated beta-kallikrein, containing a single cleavage in the heavy chain (mol wt 28,000 + 18,000) and compared it to the enzyme, alpha-kallikrein, with an intact heavy chain. The rates of inactivation by C1 inhibitor of plasma alpha- and beta-kallikreins were kinetically identical, as measured by residual amidolytic activity, after various times of incubation with the inhibitor. Both enzymes reacted completely with C1 inhibitor after 18 hours and formed identical C1 inhibitor-kallikrein complexes of mol wt 195,000. The rate of activation of factor XII by alpha-kallikrein and beta-kallikrein was similar. In contrast, the rate of cleavage of high molecular weight kininogen (HMWK) by alpha-kallikrein was at least fivefold faster and the ratio of coagulant activity to amidolytic activity was fourfold greater than for beta-kallikrein. Plasma alpha-kallikrein, at concentrations potentially achievable in plasma, induced aggregation of neutrophils, but beta-kallikrein failed to elicit this response. In addition, human neutrophils pretreated with cytochalasin B released 2.46 +/- 0.10 microgram/10(7) cells of elastase antigen, but beta-kallikrein released only 0.25 +/- 0.10 micrograms/10(7) cells. These observations suggest that cleavage of the heavy chain influences the rate of cleavage of HMWK and decreases its coagulant activity. Moreover, an intact heavy chain appears to be requisite to support the ability of kallikrein to aggregate neutrophils and release elastase.

Blood Coagulation Tests↗
PubMed1985

Assessment of Hageman factor activation in human plasma: quantification of activated Hageman factor-C1 inactivator complexes by an enzyme-linked differential antibody immunosorbent assay.

An enzyme-linked immunosorbent assay has been developed for the quantitation of activated Hageman factor-C1 inactivator (HF-C1 INH) complexes. Addition of increasing quantities of either of the major forms of activated Hageman factor (HFa or HFf) to normal plasma or to Hageman factor-deficient plasma leads to a dose-dependent increase in activated HF-C1 INH complexes. As little as 0.5 micrograms/mL of activated HF added to plasma can be detected, corresponding to activation of approximately 2% of plasma HF. The sensitivity of the assay is increased at least tenfold when complexes are formed in HF-deficient plasma, indicating competition between unactivated HF and activated HF-C1 INH complexes for binding to the antibody. Specificity is demonstrated in that addition of activated HF to hereditary angioedema plasma yields less than 1% of the activated HF-C1 INH complex formation obtained with normal plasma. Kaolin activation of HF-deficient plasma yields no detectable complex formation. Kaolin activation of prekallikrein-deficient plasma demonstrates a time-dependent increase in formation of activated HF-C1 INH complex consistent with the ability of HF in this plasma to autoactivate as the time of incubation with the surface is increased. Kaolin treatment of high-molecular weight (HMW) kininogen-deficient plasma yields an even more profound abnormality in the rate of formation of activated HF-C1 INH complexes reflecting the complex role of HMW kininogen in the initiation of contact activation. Although addition of corn inhibitor to plasma prevents activated HF-C1 INH complex formation, it does not inhibit activated HF sufficiently fast to prevent prekallikrein activation.

Blood Coagulation↗