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PubMed1999

Systemic lupus erythematosus presenting with haemorrhagic manifestation.

A 26-year-old female presented with an episode of severe mucus membrane bleeding. Investigations revealed prolonged prothrombin time (PT), and partial thromboplastin time (PTT), normal thrombin time (TT) and reptilase time, thrombocytopenia, a positive test for lupus anticoagulant (LA), as well as anti-cardiolipin antibodies (ACL). A toxicology screen for toxic drugs and coumadin was negative. Coagulation factor assays revealed low levels for factor II and XII. Low level inhibitor to factor II was demonstrated. Patient had a negative VDRL test and positive anti-nuclear antibodies (ANA). The diagnosis of acquired hypoprothrombinaemia secondary to circulating inhibitor induced by LA was made, and then the patient was started on prednisone, which led to cessation of the bleeding and normalization of PT and PTT, as well as an increase of factor II and factor XII levels. A few months later, the patient developed arthralgia and alopecia, and antibodies against double-stranded DNA were detected, and the diagnosis of systemic lupus erythematosis (SLE) was confirmed. The patient continued to have mild prolongation of PT and PTT while on a low dose of prednisone, but she had no bleeding symptoms. A computed tomography scan of the brain was carried out for unexplained central nervous system (CNS) symptoms, and it revealed mild hydrocephalus, which was thought to be part of the CNS manifestations of SLE. It was concluded that patients with SLE may present with haemostatic defects that are a result of either platelet-related causes (quantitative or qualitative) or coagulation factor deficiency secondary to circulating inhibitor, or both, in the absence of other features of SLE which may appear later.

Adult↗
PubMed1976

Identification of prekallikrein and high-molecular-weight kininogen as a complex in human plasma.

Prekallikrein and high-molecular-weight kininogen were found associated in normal human plasma at a molecular weight of 285,000 as assessed by gel filtration on Sephadex G-200. The molecular weight of prekallikrein in plasma that is deficient in high-molecular-weight kininogen was 115,000. This prekallikrein could be isolated at a molecular weight of 285,000 after plasma deficient in high-molecular-weight kininogen was combined with plasma that is congenitally deficient in prekallikrein. Addition of purified 125I-labeled prekallikrein and high-molecular-weight kininogen to the respective deficient plasma yielded a shift in the molecular weight of prekallikrein, and complex formation could be demonstrated by incubating prekallikrein with high-molecular weight kininogen. This study demonstrates that prekallikrein and high-molecular-weight kininogen are physically associated in plasma as a noncovalently linked complex and may therefore be adsorbed together during surface activation of Hageman factor. The complex is disrupted when these proteins are isolated by ion exchange chromatography.

Factor XII↗
PubMed1999

The role of factor XI in coagulation: a matter of revision.

In 1991 it was demonstrated that, besides factor XII, thrombin is capable of activating factor XI in vitro. Thrombin-dependent activation of factor XI is an integral part of the revised theoretical model of coagulation in which coagulation is initiated by the extrinsic pathway and maintained by thrombin-induced activation of clotting factors V, VIII, and XI. In this review, special interest is given to the new role of factor XI in coagulation, with emphasise on data supporting the concept of thrombin-mediated factor XI activation in vivo. Furthermore, activation of factor XI in human disease, especially atherosclerotic disease, measured by newly developed immunologic assays, is discussed. The relation of factor XI to fibrinolysis through activation of the carboxypeptidase, thrombin-activatable fibrinolysis inhibitor (TAFI) by thrombin provides an explanation for the bleeding tendency observed in factor XI-deficient patients. The probable link with factor XI-mediated TAFI activation may have clinical and therapeutic consequences and deserves further study.

Arteriosclerosis↗
PubMed2005

Causes of isolated prolonged activated partial thromboplastin time in an acute care general hospital.

INTRODUCTION: To determine the causes of isolated prolonged activated partial thromboplastin time (APTT) in an acute care general hospital setting so as to rationalise fresh frozen plasma usage. METHODS: A prospective study of consecutive patients with isolated prolonged APTT presenting to our hospital between February 2002 and January 2004 was performed. All patients had normal prothrombin time and thrombin time. For all patients, an initial 50:50 correction with plasma was done and a standard panel of tests was performed. These included detection of lupus anticoagulant using two different sensitive tests; measurement of coagulant factors VIII (FVIII), IX, XI and XII, which are involved in the intrinsic arm of haemostasis; von Willebrand factor antigen (vWF:Ag) levels and for those with FVIII levels less than 10 percent, an inhibitor assay using the Nijmegen modification of the Bethesda method. RESULTS: 177 patients were included in the study. The cohort was typical of an acute care general hospital patient population in Singapore in terms of age, sex and racial distribution. The most common cause of an isolated prolonged APTT in our study was the presence of lupus anticoagulant (53.1 percent of cases). In 31.6 percent of cases, obvious cause could be detected after our panel of tests. These patients mostly had mildly prolonged APTT that could be both correctable and non-correctable by normal plasma. Prolonged APTT due to factor deficiency was relatively rare with those that may potentially cause haemorrhagic problems only accounting for 4.5 percent of cases. CONCLUSION: Our study suggests that most of the causes of isolated prolonged APTT do not lead to haemorrhagic complications. In fact, in a majority, it may signify an underlying thrombophilic condition. As a result, prolongation of APTT should be fully investigated and correction with fresh frozen plasma should be used only when appropriate.

Acute Disease↗
PubMedDate not supplied

A therapeutic, highly purified factor XI concentrate from human plasma.

A highly purified factor XI (FXI) concentrate was prepared from human plasma by a process comprising a filter adsorption step and chromatography on a cation exchange resin. The freeze-dried FXI, which solubilized quickly, had high specific activity (130-150 U/mg protein), high potency (approx. 100 U/mL), and excellent stability for at least 24 hours at room temperature in the liquid state. The overall recovery was about 220 U of FXI per liter of plasma. Minor protein contaminants (C1-inhibitor, fibronectin, IgG, and alpha-2-macroglobulin) were found to be between 0.13 and 0.46 mg per 1000 U of FXI. Fibrinogen and relevant coagulation factors (factors II, V, VII, IX, X, XII, XIII, and VIII/von Willebrand factor) were undetectable, as evidenced by immunologic and immunoelectrophoretic data. Components of the kinin system were present in trace amounts or were undetectable. No evidence of activated factors such as factors Xa and IXa was found. Proteolytic activity, as assessed by S-2288 chromogenic substrate, was negligible and thrombin was undetectable. A solvent-detergent treatment was included prior to chromatographic purification to enhance viral safety against lipid-enveloped viruses. In vitro and in vivo animal studies demonstrated the absence of thrombogenic, hypotensive, or toxic effects. No thrombogenic activity was found in the Wessler model in rabbits at doses of 900 to 1100 U of FXI per kg of body weight. This FXI preparation could be beneficial in substitution therapy of congenital or acquired FXI deficiency, especially as a way to avoid the use of fresh-frozen plasma.

Animals↗
PubMed2003

Kallikrein modification with affinity to IgG present in higher amounts than normal in plasma from patients with Crohn's disease.

This study presents immunological and functional evidence to suggest that the activation of prekallikrein (PK) in human plasma yields two modifications of kallikrein. One of these modifications showed amidolytic properties strongly deviating from those registered for the main part of the enzyme. The substrates were S-2302, Bz-Pro-Phe-Arg-pNA, S-2366 and S-2222. In PAGE immunoblots the PK heavy chain mAb 13G11 was found to detect the kallikrein 85 kD double band and bands with mol. weights of about 152 and 135 kD. Such a 152 kD band could be removed together with an IgG fraction on a Protein G column. In this study the kallikrein identity was confirmed by an estimation of the levels obtained in amidolytic assays of mixtures of normal plasma and plasma deficient in FXI, which in immunological assays showed a PK level of 140-150%, of normal. A comparison in amidolytic assays of normal plasma and plasma from patients with Crohn's disease showed that patients' plasma contained a significantly higher level than normal of modified kallikrein. An IgG removal procedure removed all modified kallikrein, and did not affect ordinary kallikrein levels.

Amidohydrolases↗
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↗
PubMed1990

The haemostatic balance in groups of thrombosis-prone patients. With particular reference to fibrinolysis in patients with myocardial infarction.

The concept of the haemostatic balance was reviewed, and its potential role in the regulation of tissue repair and the pathogenesis of thrombotic processes was surveyed. Physiological activation of coagulation appears to be dominated by effects of degenerated and injured cells of the vascular wall causing local release of thromboplastin and exposition of activating surfaces. Inhibition of coagulation impairs its progression and the non-thrombogenic nature of the normal endothelium is chiefly caused by the binding of inhibitory components (antithrombin-III, protein C) to specific receptor sites. Physiological activation of fibrinolysis appears to be triggered by and limited to the fibrin because of a specific affinity to fibrin of plasminogen and plasminogen activators. Systemic activation of fibrinolysis is prevented by primary (alpha 2-antiplasmin) and secondary (alpha 2-macroglobulin, alpha 1-antitrypsin) plasmin inhibitors. A plasminogen binding protein (histidine-rich glycoprotein), plasmin inhibitors and activator inhibitors appear to contribute to the regulation of the initial phase of fibrinolysis. A deviation from normal of the dynamic balance, regulating fibrin formation and resolution, may lead to a haemorrhagic and/or a thrombophilic state. Described were the optimization of selected methods for assessment of variables involved in the haemostatic balance. An overestimation of plasminogen concentrations in plasma may occur in patients with elevated levels of fibrinogen or fibrin degradation products, when using assays based on the activation of plasminogen by streptokinase followed by the hydrolysis of a synthetic chromogenic substrate. This source of error could be eliminated by presence of fibrinogen in excess in the plasminogen assay, thereby securing maximum stimulation of the plasminogen-streptokinase complex. The presence of cryoglobulin in plasma interferes with the assessment in euglobulins of plasminogen activator activities. Experiments indicate that tissue-type plasminogen activator adsorb cryoglobulins and that a cold-promoted activation of the factor XII-dependent proactivator system of fibrinolysis is related to the presence of cryoglobulins. Experiments supported the existence of an as yet not characterized factor XII-dependent proactivator. Strictly optimized procedures for the preparation of euglobulins for the accurate determination of plasminogen activators were recommended. The determination of plasminogen activator inhibition in plasma was optimized and simplified. The amidolytic assay of antithrombin-III was shown to be influenced by adsorption to laboratory utensils and aggregation of thrombin. This error could be corrected by protection with additives (Tween 80, polyethyleneglycol 6,000), which also improved the solubility of the chromogenic substrates in aqueous media. The role of thrombosis in myocardial infarction was reviewed.(ABSTRACT TRUNCATED AT 400 WORDS)

Antithrombin III↗
PubMed1984

In vitro activation of the contact (Hageman factor) system of plasma by heparin and chondroitin sulfate E.

A large number of negatively charged macromolecules, including DNA, glycosaminoglycans, and proteoglycans, were tested as possible activators of the contact (Hageman factor) system in vitro. Activation was assessed by conversion of prekallikrein to kallikrein, as determined by amidolytic assay and by cleavage of 125I-Hageman factor into 52,000- and 28,000-dalton fragments. Of particular interest to these studies, heparin proteoglycan and glycosaminoglycan from rat peritoneal mast cells, and squid chondroitin sulfate E, which is representative of the glycosaminoglycan from cultured mouse bone marrow derived mast cells, induced the reciprocal activation between Hageman factor and prekallikrein. In addition, naturally occurring heparin glycosaminoglycans from pig mucosa, bovine lung, and rat mast cells also induced activation. In contrast, native connective tissue matrix glycosaminoglycans and proteoglycans from several sources were inactive, although when one such chondroitin sulfate was further sulfated in vitro, it gained activity. When the negative charge of the activating agents was blocked by the addition of hexadimethrine bromide, the cleavage of 125I-Hageman factor in the presence of prekallikrein was prevented. The active negatively charged macromolecules induced cleavage of 125I-high molecular weight kininogen in normal plasma but not in Hageman factor-deficient or prekallikrein-deficient plasmas. Reconstitution of prekallikrein-deficient plasma with purified prekallikrein restored the kininogen cleavage upon addition of the active proteoglycans. These results suggest that both heparin from connective tissue mast cells and highly sulfated chondroitin sulfate E from cultured mouse bone marrow derived mast cells (which are considered synonomous with mucosal mast cells) could activate the contact system of plasma subsequent to an activation secretion response.

Animals↗
PubMed1984

Immunoreactive tissue kallikrein in human serum.

Human urinary kallikrein and an antiserum to it raised in the rabbit were used to detect and quantitate immunoreactive tissue kallikrein in human serum. Both 125I-labeled kallikrein and the unlabeled purified enzyme appear complexed to higher molecular weight entities in serum, but specific binding between radiolabeled enzyme and antiserum was unaffected by the presence of serum or plasma. Parallelism to standard displacement curves was always seen with radioimmunoassay of normal sera as well as with human mixed saliva or pancreatic extracts. Assay sensitivity is 160 pg/ml of serum, or 16 pg per tube. Purified plasma kallikrein or prekallikrein in concentrations up to 10 micrograms/ml showed no displacement. Acetone-kaolin activation of plasma produced the expected 30-fold increase in Tos-Arg-OMe esterase activity but no change in immunoreactive tissue kallikrein levels. Serum concentrations were 3.8 +/- 0.7 (mean +/- SE) ng/ml in 21 normal volunteers, and were similar in patients with Fletcher trait or Hageman factor deficiency. Significantly increased serum concentrations were seen with long-term low dietary sodium intake or acute forms of pancreatitis. Although the relation of this immunoreactive material to any active tissue kallikrein within the circulation remains to be determined, our studies provide a new parameter for the assessment of a system repeatedly suggested to have some role in regulation of vascular resistance.

Adult↗
PubMed1973

The fibrinolytic pathway of human plasma. II. The generation of chemotactic activity by activation of plasminogen proactivator.

The conversion of plasminogen proactivator to plasminogen activator by Hageman factor fragments results in the generation of chemotactic activity for human neutrophils. This chemotactic activity can be distinguished from that generated by Hageman factor activation of prekallikrein and is demonstrable in plasma that is genetically deficient in prekallikrein (Fletcher factor deficiency). Both the plasminogen-activating activity and chemotactic activity produced by the interaction of Hageman factor fragments and plasminogen proactivator to yield plasminogen activator were inhibited by diisopropyl fluorophosphate (DFP) indicating an essential role for the enzymatic site in both these activities. The finding that the plasminogen proactivator tolerated a dose of DFP, which completely inactivated the plasminogen activator, reveals that the active site is protected in the precursor protein.

Blood↗
PubMed1988

Role of the plasma contact system in the pathogenesis of experimental anti-GBM glomerulonephritis.

To study the participation of the Hageman factor-related contact system of plasma in the pathogenesis of glomerulonephritis (GN), an anti-BM GN was induced in a group of 10 normal Brown Norway rats and another of seven Brown Norway BN/Mai Pfd f rats. The latter strain is characterized by a congenital deficiency of plasma prekallikrein and of high-molecular weight kininogen, with lengthening of the activated partial thromboplastin time. In the deficient group, one animal developed crescents in less than 25% of glomeruli, five in 25-50% and one in 50-75%. In the group of normal rats, extracapillary proliferation was of greater severity: one animal showed crescents in less than 25% of glomeruli, two in 50-75% and five in more than 75% of glomeruli. Although in both groups intense glomerular fibrin deposition was documented, the intensity of these deposits was less severe in the deficient animals. These data suggest, in the first place, that functional integrity of the contact system is not a necessary requirement for glomerular fibrinogenesis, other mechanisms being implicated in this phenomenon. On the other hand, this functional deficit has exerted a protective effect on crescent formation, which suggests that the contact system can play a role as a mediator of injury in glomerulonephritis, perhaps through the release of contact system-dependent mediators of inflammation.

Animals↗
PubMed1983

Studies of C1 inactivator-plasma kallikrein complexes in purified systems and in plasma.

An enzyme-linked immunosorbent assay (ELISA) has been developed for the quantification of C1 inactivator-kallikrein (C1In-K) complexes. The formation of complexes assayed by this method parallelled the inhibition of plasma kallikrein esterase activity by C1 inactivator in purified systems. C1In-K complexes were detected when a final concentration of 5.7 nM plasma kallikrein was added to plasma, equivalent to the activation of 1% of the plasma prekallikrein. Exogenous Hageman factor fragment added to plasma induced the rapid formation of C1In-K complexes, whereas there was an appreciable delay when the plasma contact system was activated by the addition of kaolin. In both systems, the rate of formation and final amount of complex generated were directly related to the concentration of Hageman factor fragment or of kaolin added, indicating that this proteolytic pathway is tightly regulated. C1In-K complexes were not generated by kaolin in plasma congenitally deficient in Hageman factor or prekallikrein or by kallikrein in hereditary angioedema plasma deficient in C1 inactivator, thus confirming the specificity of the assay. Sucrose gradient ultracentrifugation studies showed plasma C1In-K complexes to have a molecular weight consistent with a 1:1 molar complex. In contrast, the complex displayed an anomalously high molecular weight on gel filtration chromatography. These data demonstrate that a sensitive and specific probe has been developed for documenting plasma kallikrein activation.

Angioedema↗
PubMed1977

Purification of high molecular weight kininogen and the role of this agent in blood coagulation.

Recent studies of individuals with high molecular weight (HMW) kininogen deficiency established the importance of this plasma protein for in vitro initiation of blood coagulation. In the present study, HMW-kininogen was highly purified from human plasma by monitoring its clot-promoting activity, using Fitzgerald trait plasma as a substrate. This preparation of HMW-kininogen revealed a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (mol wt: 120,000) and released 1% of its weight as bradykinin upon incubation with plasma kallikrein. HMW-kininogen specifically repaired impaired surface-mediated plasma reactions of Fitzgerald trait plasma, but did not affect those of Hageman trait and Fletcher trait plasma. Kinin release from HMW-kininogen by trypsin, but not by plasma kallikrein, resulted in total loss of clot-promoting activity. No inhibitors of coagulation were found when all kinin activity was removed from HMW-kininogen by trypsin. The roles of HMW-kininogen, Hageman factor (HF, Factor XII), plasma prekallikrein (Fletcher factor), and plasma thromboplastin antecedent (PTA, Factor XI) in blood coagulation were studied in a purified system. HMW-kininogen was absolutely required for activation of PTA by HF and ellagic acid. The yield of activated PTA was proportional to the amount of HF, HMW-kininogen, and PTA in the mixtures, suggesting that, to activate PTA, these three proteins might form a complex in the presence of ellagic acid. No fragmentation of HF was found under these conditions. In contrast to HF, HF-fragments (mol wt: 30,000) activated PTA in the absence of HMW-kininogen and ellagic acid. Thus, it appears that in the present study PTA was activated in two distinct ways. Which pathway is the major one in whole plasma remains to be determined.

Blood Coagulation↗
PubMed2006

Procoagulant activity of surface-immobilized Hageman factor.

Procoagulant activity of surface-immobilized coagulation factor XIIa (activated Hageman factor) is reported. Activity of FXIIa immobilized onto the surfaces of three silanized-glass procoagulants spanning a wide range of wettability was assayed in normal and FXII-deficient plasmas. Previously published mathematical models were used to characterize the procoagulant activity of protein-immobilized materials and soluble enzymes. Results show that FXIIa activity is unrelated to underlying procoagulant surface chemistry and is similar to soluble FXIIa activity. The uninfluential role of the surface on FXIIa suggests that the solid surface activates FXII in biomaterial-induced blood coagulation but is not otherwise involved in FXIIa activity as described by the classical mechanism.

Adsorption↗
PubMed1982

A protease-like permeability factor in guinea pig skin: immunologic identity with plasma Hageman factor.

Vascular permeability enhancement activity of the protease-like permeability factor derived from guinea pig skin and of active guinea pig Hageman factor (beta HFa) were both inhibited by anti-guinea pig Hageman factor rabbit F(ab')2 antibody. The permeability activity of both factors was also absorbed on anti-Hageman factor F(ab')2-Sepharose beads. The latent form of the permeability factor derived from skin extracts produced a single immunoprecipitation line with anti-Hageman factor and gave a reaction of identity with a precipitation band developing between purified Hageman factor and anti-Hageman factor. The latent permeability factor in the fraction corrected the clotting activity of Hageman-factor-deficient human plasma. The clotting activity was also blocked by anti-Hageman factor F(ab')2 antibody. From these results, it was concluded that the skin permeability factor was immunologically and functionally indistinguishable from Hageman factor of plasma. Extracts were obtained from skin of guinea pigs given intravenous injections of 125I-guinea pig Hageman factor immediately before sacrifice to calculate the amount of Hageman factor in the extravascular tissue space of the skin. The pseudoglobulin fractions of the extracts containing a concentration of Hageman factor of approximately 9 microgram of Hageman factor per gram of skin. This was determined both by immunologic means and procoagulant activity. Only 4% of the Hageman factor in the extract was obtained from the intravascular plasma volume of the skin.

Animals↗
PubMed1987

A new assay for high molecular weight kininogen in human plasma using a chromogenic substrate.

High molecular weight kininogen (HK), the cofactor of contact-activated plasma proteolysis, is currently assayed by coagulant or immunological methods. The former is limited by the need for rare, congenitally-deficient plasma and a high coefficient of variation (CV), and the latter, by failure to distinguish nonfunctional protein. The surface activation of factor XI requires HK as its cofactor to transport its zymogen form to a negatively-charged surface where it is converted to its enzymatic form by factor XIIa. Based on this principle, we developed an assay for HK using the chromogenic substrate pyroGlu-Pro-Arg-p-nitroanilide (S-2366, KabiVitrum), which is hydrolyzed by factor XIa. Plasma is first acidified to inactivate protease inhibitors. After neutralization and dilution, the plasma is incubated with an excess of factor XI, factor XIIa, and soybean trypsin inhibitor (to inactivate generated kallikrein), in the presence of a negatively-charged surface (kaolin) in order to form factor XIa. EDTA is included in the buffer to prevent calcium-dependent reactions. This activation process is stopped by adding corn trypsin inhibitor to inactivate the enzyme in this reaction, factor XIIa. Then, S-2366 is added and is hydrolyzed by the factor XIa that was formed. Since factor XI and factor XIIa are in excess of the concentration of HK in the diluted plasma, HK is the rate-limiting protein in this assay for the formation of factor XIa (after subtracting the small amount of factor XIa generated in the absence of HK). The assay is specific for HK, since no activity is detected in kininogen-deficient plasma, and when compared with the HK coagulant assay, r = 0.95 and slope = 0.95. The mean of 21 normal donors was 0.98 U/ml (range 0.68 - 1.28 U/ml) as compared with pooled, normal plasma. The CV for 1 U/ml HK for the chromogenic assay was 2% as compared with 9.5% for the coagulant assay. When purified reagents become commercially available, this assay could prove useful in clinical laboratories or intensive care units for monitoring the progression of various disease states in which contact activation occurs.

Colorimetry↗
PubMed1971

A prealbumin activator of prekallikrein. II. Derivation of activators of prekallikrein from active Hageman factor by digestion with plasmin.

Activation of a plasma fraction containing unactivated Hageman factor and prekallikrein followed by chromatography of this fraction on DEAE-cellulose revealed four peaks having bradykinin-generating activity. Peak 1 contained kallikrein; peaks 2-3, 4, and 5 each contained prekallikrein-activating activity. Elution of peaks 2-3, 4, and 5 from disc gels after electrophoresis at pH 9.3 revealed peaks of prekallikrein-activating activity located at 5-8, 11-12, 15-16, and 20-26 mm, each of which was associated with a peak of clot-promoting activity which specifically corrected Hageman factor deficiency. Conversion of peak 2 to peaks 3, 4, and 5 was associated with a progressive decrease in size, increase in net negative charge, increased prekallikrein-activating activity, and decreased ability to correct Hageman factor deficiency. Plasminogen and plasmin were found on a DEAE-cellulose chromatogram of serum overlapping peaks 2 and 3. Incubation of active Hageman factor with streptokinase-activated plasminogen resulted in enhanced ability of the mixture to activate prekallikrein. Assessment of the products of this reaction by disc gel electrophoresis demonstrated the formation of the prealbumin prekallikrein activator corresponding to the major prekallikrein activator generated by contact activation of human plasma. The conversion of plasminogen to plasmin and the subsequent cleavage of Hageman factor by plasmin to form activators of prekallikrein represents one pathway in which coagulation, fibrinolysis, and inflammation are linked.

Bradykinin↗