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PubMed1979

Isolation and characterization of bovine plasma prekallikrein (Fletcher factor).

Prekallikrein (Fletcher factor) has been purified from bovine plasma approximately 25 000-fold with an overall yield of 14%. Purification steps included ammonium sulfate fractionation and column chromatography on heparin-agarose, DEAE-Sephadex, CM-Sephadex, benzamidine-agarose, and arginine methyl ester-agarose. The purified protein was homogeneous as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and amino-terminal sequence analysis. Bovine plasma prekallikrein is a glycoprotein with a molecular weight of 82 000 as determined by sedimentation equilibrium centrifugation. It contains 12.9% carbohydrate, including 6.2% hexose, 4.5% N-acetylglucosamine, and 2.2% N-acetylneuraminic acid. Prekallikrein is a single polypeptide chain with an amino-terminal sequence of Gly-Cys-Leu-Thr-Gln-Leu-Tyr-His-Asn-Ile-Phe-Phe-Arg-Gly-Gly. This sequence is homologous to the amino-terminal sequence of human factor XI (plasma thromboplastin antecedent). Both prekallikrein and kallikrein require kaolin to correct Fletcher factor deficient plasma. Kallikrein, however, has a specific activity 3.5 times greater than prekallikrein. Prekallikrein does not correct plasma deficient in factor XII (Hageman factor), factor XI, or high molecular weight kininogen (Fitzgerald factor).

Amino Acid Sequence↗
PubMed2001

Activation of plasma coagulation by retransfusion of unwashed drainage blood after hip joint arthroplasty: a prospective study.

Twelve patients undergoing cementless hip joint arthroplasty were retransfused with unwashed drainage blood collected postoperatively. Global coagulation parameters, coagulation factors (factor V:C, factor VIII:C, activated factor XII, and factor XIII) and markers of thrombin generation (F1+2 Fibrin split products, thrombin-antithrombin complexes), fibrin generation (fibrinogen and fibrin degradation products), and fibrinolysis (D-dimers, thrombin degradation products, plasminogen) were determined. High levels of factor XIIa, thrombin and fibrin generation markers, and markers of fibrinolysis were present in the shed blood. After retransfusion (mean, 433 mL), increased levels of these markers together with decreased values for factor XIII and plasminogen were indicative of renewed clot formation and fibrinolysis in the circulation. These changes were highly significant compared with preretransfusion values. The unwashed drainage blood contained high levels of procoagulation material and induced an activation of the plasma coagulation pathway with renewed clot formation and fibrinolysis in the patients.

Aged↗
PubMed1994

Mechanisms, markers and management of coagulation activation.

Sensitive and specific laboratory methods are now available to detect and diagnose states of coagulation activation, defined as a procoagulant imbalance between the production and inhibition of enzymes in the coagulation system short of fibrin deposition. Although most coagulation enzymes cannot be measured specifically and accurately, assays for activated factor XII and factor VII have recently become available. Activated protein C, the active enzyme of a major anticoagulant pathway, can also be measured. Indirect approaches to the detection of coagulation activation are to measure the plasma levels of peptides released from coagulation zymogens when they are converted into active enzymes and the stable complexes formed in plasma when such enzymes are neutralized by their naturally-occurring inhibitors. These assay methods have dramatically improved our understanding of the mechanistic role of coagulation activation in health and disease. However, their clinical predictive value and usefulness for choosing and monitoring antithrombotic therapy still need to be defined in prospective clinical studies.

Blood Coagulation↗
PubMed1983

Purification of prekallikrein from porcine plasma and its conversion to active kallikrein.

Plasma prekallikrein, a precursor protein of kallikrein [EC 3.4.21.8], was highly purified from porcine plasma by chromatography on a DEAE-Sephadex A-50 column, followed by rechromatography on a DEAE-Sephadex A-50 column, chromatography on a CM-Sephadex C-50 column and affinity chromatography on a p-aminobenzamidine-epsilon-aminocaproic acid-Sepharose 4B column. By this procedure, 3.3 mg of purified material was obtained from 1.6 liters of porcine plasma and about 240-fold purification was achieved from the first DEAE-Sephadex A-50 chromatography. The purified protein was found to give a single band on sodium dodecyl sulfate (SDS)-polyacrylamide gel disc electrophoresis. This preparation did not contain kallikrein, Factor XII (Hageman factor) of the blood coagulation system, high molecular weight (HMW) kininogen or plasma kininase. Thus, the material is presumed to be functionally pure. The molecular weight of prekallikrein was estimated to be about 88,000 by SDS-polyacrylamide gel electrophoresis, and prekallikrein consists of a single polypeptide chain. Activation of prekallikrein by trypsin [EC 3.4.21.4] was found to involve the cleavage of a single peptide bond on the disulfide-bridged polypeptide chain, and no change of molecular weight was observed during the activation. This trypsin-activated kallikrein released kinin rapidly from bovine HMW kininogen. However, liberation of kinin was extremely slow from bovine low molecular weight (LMW) kininogen. The kallikrein activity was inhibited by soybean trypsin inhibitor (SBTI) and Trasylol, but not by Polybrene or egg-white trypsin inhibitor (EWTI).

Animals↗
PubMed1989

Coagulation, fibrinolysis, and kallikrein systems in sepsis: relation to outcome.

Fatal multiple organ failure after severe infection may be related to an early activation of protease cascade systems. This study aimed to relate changes in coagulation, fibrinolysis, and kallikrein to shock and outcome. Of 53 patients with severe infection, 30 did not develop shock, 12 survived septic shock, and 11 died from organ failure after septic shock. No patient had overt disseminated intravascular coagulation. We measured 17 components of the coagulation/fibrinolysis/kallikrein pathways on admission and on the next 2 days. High values for fibrinogen, factor VIII:C, von Willebrand factor antigen, and D-dimer were seen in all patients; factor XII, prekallikrein, factor VII, antithrombin, protein C, and fibronectin were low. The patients thus appeared to be hypercoagulable. These disturbances were more pronounced in septic shock survivors, who also had low plasminogen and antiplasmin, indicating ongoing fibrinolysis. Nonsurvivors of sepsis were distinguished mainly by high plasminogen activator inhibitor values; this suggests an impaired functional fibrinolysis in fatal sepsis, with possible therapeutic implications. Cryoprecipitate infusion increased the fibronectin concentration, but did not influence the other factors studied.

Adult↗
PubMed2005

Clotting time analysis of citrated blood samples is strongly affected by the tube used for blood sampling.

Our aim was to establish whether differences in clotting times for recalcified blood and plasma samples might be explained by the use of different blood collection tubes. Samples obtained from different plastic vacuum tubes were recalcified and clotting times determined by free oscillation rheometry. The clotting times for blood collected in Vacutainer (Becton Dickinson, Rutherford, New Jersey, USA) or Vacuette (Greiner Bio-One, Kremsmünster, Austria) tubes decreased with time, with maximal effect after 30 min. Blood from Monovette (Sarstedt, Nümbrecht, Germany) tubes displayed longer clotting times, which did not decrease with time. Clotting times for plasma prepared after 1 h storage in Vacutainer or Vacuette tubes were unaffected by subsequent addition of corn trypsin inhibitor to inhibit factor XIIa, although an antibody against factor XI prolonged the clotting time markedly. In Monovette plasma, both corn trypsin inhibitor and anti-factor XI effectively prolonged the clotting time. When corn trypsin inhibitor or anti-factor XI was added to the tubes before blood collection, but both additions clearly prolonged the clotting times in all types of tubes, even though corn trypsin inhibitor was less effective in whole blood. Antibodies against human tissue factor did not affect the clotting times. The amounts of platelet or leukocyte microparticles in plasma were low and similar in all tubes. This indicates that blood collection in Vacutainer or Vacuette tubes induces a rapid activation of factor XII and factor XI.

Antibodies↗
PubMed1976

Studies on the blood clotting and fibrinolytic system in the plasma from a sei (baleen) whale.

Blood clotting and fibrinolytic systems were studied in the plasma of a sei whale (Balaenoptera borealis). The sei whale belongs to the suborder baleen whales of the order Cetacea. Whale plasma had a greatly prolonged kaolin-activated partial thromboplastin time and was deficient in Hageman factor (factor XII), Fletcher factor (a plasma prekallikrein), and PTA (factor XI). All other clotting factor activities were present in amounts comparable to that of normal human plasma. Whale plasminogen was activated by human urokinase, but not by streptokinase. Whale plasma contained inhibitory activities against thrombin, activated Stuart factor, activated PTA, activated Fletcher factor, and plasmin.

Animals↗
PubMed2001

Kinetic analysis of a simplified scheme of autocatalytic zymogen activation.

Proteolytic enzymes are usually biosynthesized as somewhat larger inactive precursors known as zymogens. These zymogens must undergo an activation process, usually a limited proteolysis, to attain their catalytic activity. When the activating enzyme and the activated enzyme coincide, the process is an autocatalytic zymogen activation. In the present study, a kinetic analysis of the entire progress curve for the autocatalytic zymogen activation reactions is presented. On the basis of the kinetic equations, a novel procedure is developed to evaluate the kinetic parameters of the reactions. This procedure is particularly useful for the fast zymogen autoactivation reactions. As two examples, the novel procedure is used to analyse the autocatalytic activation of bovine trypsinogen and human blood coagulation factor XII (Hageman factor).

Animals↗
PubMed1979

Contact activation of plasma: structure-activity relationships of human high molecular weight kininogen.

Human high MW kininogen can be isolated as a single polypeptide chain of 110,000 MW. Purified human plasma kallikrein cleaves this molecule to give a disulfide-linked, two chain molecule, free of kinin, that retains full clotting activity. Following reduction and carboxymethylation of the two chain molecule, a light chain can be isolated that quantitatively retains the full coagulant activity of the native molecule. During contact activation in normal human plasma a rapid cleavage of high MW kininogen along with kinin liberation occurs in a reaction that is dependent upon the presence of prekallikrein and Factor XII (Hageman factor).

Blood Coagulation↗
PubMedDate not supplied

[Secretion of membrane-bound serine proteinases by polymorphonuclear leukocytes during adhesion to various types of receptor-dependent and receptor-independent sorbents].

A high level of the membrane-bound proteinase (LMP) secretion by human polymorphonuclear leukocytes (up to 680 nmol/min/ml with N-benzoyl-L-arg-EE as a substrate) was shown during the cell adhesion to receptor-dependent (immobilized aggregates of IgG and C3b) and receptor-independent (DEAE-Sephadex and polymethyl methacrylate) absorbents. Incubation medium contained 6.10(6) cells/ml. The rate of secretion reached the maximal level during 15 min although its level was already high to the 5 min of C3b- and hydrophobic surface-induced activation (491 +/- 55 and 382 nmol/min, respectively). The high level of LMP secretion coincided with the peak of luminol-dependent chemoluminescence during the receptor-dependent adhesion, but did not correlate with a low level of luminescence in the receptor-independent adhesion. Localization of LMP in latent form in neutrophil membrane was shown earlier; the enzyme activation may occur due to effect of polycationic molecules of bovine tissue proteinase inhibitor of Kunitz type, protamine sulfate, alkaline fraction of ampholines. The enzyme (with BAEE as a substrate) was identified as serine proteinase of the trypsin-like type which activated Hageman factor (the XII factor of clotting system) and demonstrated the kininogenase activity. Only slight elastase-like activity was detected after incubation of neutrophils with all the adsorbents studied (0-2 nmol/min/ml with MeOSucAlaAlaProValpNA as a substrate). Chymotrypsin-like activity achieved maximum only by 30 min of activation with all the types of adsorbents (up to 270 nmol/min/ml with N-benzoyl-Tyr-EE as a substrate); this suggests impairment of azurophilic granules and appearance of cathepsin G.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1996

Phosphatase 2A participates in interferon-gamma's induced upregulation of C1 inhibitor mRNA expression.

C1 inhibitor (C1 INH) is the major inhibitor of the proteolytically active subcomponents of C1, kallikrein, activated forms of factor XII, and factor XIa in plasma. We determined the mechanism(s) how interferon-gamma (IFN-gamma) regulates C1 INH mRNA expression in HepG2 cells. Cycloheximide or anisomycin treatment alone did not increase C1 INH mRNA nor did it potentiate C1 INH mRNA expression after IFN-gamma stimulation. C1 INH mRNA levels on Northern blot from untreated and IFN-gamma-treated cells did not change for more than 20 hours after actinomycin D treatment. Actinomycin D and 5,6-dichloro-1-beta-ribofuranosylbenzimidazole abolished IFN-gamma-induced C1 INH mRNA expression. Relatively more C1 INH mRNA precursor (heterogeneous nuclear RNA [hnRNA]) was detected in total RNA from IFN-gamma-treated HepG2 cells than unstimulated cells. Treatment of HepG2 cells with the phosphatase 1 and 2A inhibitors, okadaic acid (> or = 50 nmol/L) and calyculin (> or = 25 nmol/L), decreased IFN-gamma's ability to upregulated C1 INH mRNA. The phosphatase 2A inhibitor, cantharidin (> or = 10 micromol/L), also blocked the IFN-gamma induction of the C1 INH gene. In HepG2 cells total phosphatase 2A activity was significantly increased by C6 ceramide but not IFN-gamma. However, C6 ceramide itself did not increase C1 INH mRNA expression. These data indicate that phosphatase 2A is required to dephosphorylate a substrate in order for IFN-gamma to induce the transcriptional upregulation of C1 INH mRNA, but phosphatase 2A is not a direct stimulator of C1 INH gene expression.

Complement C1 Inactivator Proteins↗
PubMed1998

Contradictory functions of sulfatide in the blood coagulation system as coagulant and anticoagulant.

Sulfatide (galactosylceramide I3 -sulfate) has been reported to activate blood coagulation factor XII (Hageman factor), which suggests that it exhibits coagulant activity (Fujikama et al., 1980 Biochemistry 19, 1322-1330) However, sulfatide administered into animals as a bolus shot without subsequent thrombus formation, prolonged conventional clotting times and bleeding time (Hara et al., 1996 Glycoconjugate J. 13, 187-194). These findings suggest that it may exhibit anticoagulant rather than coagulant activity. Following this suggestion we found in vitro that binding of sulfatide to fibrinogen resulted in disturbance of fibrin formation. To examine a possible pharmacological effect of sulfatide on blood coagulation in vivo we continuously infused sulfatide into rats through plastic cannulae and found formation of giant thrombi around the tips of the cannulae. These data suggest that sulfatide may exhibit contradictory functions in the blood coagulation system.

Animals↗
PubMed1991

Studies on the contact system of coagulation during therapy with high doses of recombinant IL-2: implications for septic shock.

Patients treated with high doses of interleukin-2 (IL-2) because of cancer, develop hemodynamic and vasopermeability changes, that resemble those observed in sepsis. These patients thus provide a unique opportunity to study the early events in the development of septic shock. We analysed the changes that occurred in the contact system of coagulation in plasma from 4 patients, who together received seven 12-day cycles of high doses of IL-2. Levels of factor XII and prekallikrein during the cycles progressively fell to 50 and 30% of their initial levels, respectively, whereas significant increases in plasma factor XIIa- and kallikrein-C1-inhibitor complexes were not observed (in 3 out of 211 samples slightly increased levels of both complexes were found). The reductions in factor XII and prekallikrein were only in part due to protein leakage, since levels were still significantly lower, i.e., 80 and 50%, respectively, when corrected for albumin decreases. Levels of high molecular weight kininogen (HMWK) also decreased during IL-2 therapy, however, this decrease paralleled that of albumin. SDS-PAGE analysis of plasma HMWK did not reveal increased cleavage of this protein. The reduction of factor XII and prekallikrein, corrected for protein leakage, significantly correlated with albumin levels and inversely with daily cumulative weight gain in the patients. Thus, we demonstrate that factor XII and prekallikrein decrease during IL-2 therapy. As these decreases, already observed after 1 day treatment, were disproportional to that of albumin, a negative acute phase reactant, and correlated with signs of the vascular leak syndrome, we favor the explanation that they reflected activation rather than a decreased synthesis of the contact system proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1982

Kallikrein and prekallikrein levels in a large number of congenital clotting deficiencies and abnormalities.

Kallicrein (K) and prekallicrein (PK) were assayed in a large number of cases with congenitial clotting factor defects. Patients with factor XII deficiency were separated from other clotting abnormalities. The results were compared with a control group of normal subjects. We found significantly reduced PK activity levels in the factor XII deficient group. Although less evident, the reduction of PK activity in the group of other clotting defects was modest, however, not due to a factor VII defect. In our study we found that in the absence of factor XII, PK is not activated. Further studies will be necessary to show if PK activation is altered or reduced in other congenital clotting abnormalities.

Adolescent↗
PubMed1997

Mast cell derived heparin activates the contact system: a link to kinin generation in allergic reactions.

Contact activation occurs when plasma comes in contact with negatively charged manmade surfaces but no substance that initiates contact activation in vivo has been identified. We have isolated a mast cell heparin proteoglycan (MC-HepPG) from a Furth mouse mastocytoma-derived cell line that is analogous to human tissue-type mast cell HepPG. This material and other glycosaminoglycans (GAGs) were tested for their ability to accelerate the reciprocal activation of factor XII and prekallikrein and the autoactivation of factor XII. Quantitative analysis showed the MC-HepPG to be as active as dextran sulfate on a weight basis; hog intestine heparin, dermatan sulfate, keratan polysulfate and chondroitin sulfate C were less active, other sulfated polysaccharides were essentially inactive. Incubation of MC-HepPG in 1:4 diluted plasma resulted in complete cleavage of high molecular weight kininogen in a factor XII-dependent reaction. All of the MC-HepPG dependent reactions described above were inhibited by preincubation of MC-HepPG with heparinase I and II but not by pretreatment with heparitinase, chondroitinase ABC or the serine protease inhibitor aPMSF thus indicating that heparin proteoglycan is indeed acting as an initiating 'surface'. We analysed the proteoglycan preparation by HPLC gel filtration. Fractions spanning a molecular weight range of > 400000-8000 were active initiators. Comparison of the chromatograms obtained before and after cleavage of GAG side chains from the protein core suggested that dissociated GAGs in the MW range 69000-17000 are the most active species rather than the complete proteoglycan. MC-HepPG GAGs therefore represent a physiologic macromolecule with activity comparable to non-physiological surfaces in a purified system and with the capability to induce activation of the contact system in diluted plasma. Its ability to promote kinin generation links cellular and humoral inflammatory responses in the perivasculature and provides a possible explanation for the elevated kinin levels observed after allergen exposure.

Animals↗
PubMed1982

The contact activation mechanism in human plasma: activation induced by dextran sulfate.

Incubation of normal human plasma with dextran sulfate for 7 min at 4 degrees C generates kallikrein amidolytic activity. No kallikrein activity is generated in factor XII or prekallikrein-deficient plasma and only small amounts (8%) in high molecular weight (HMW) kininogen-deficient plasma. Addition of specific antisera directed against prekallikrein or HMW kininogen to normal plasma blocked the generation of kallikrein activity by dextran sulfate. Thus, factor XII, prekallikrein, and HMW kininogen are essential components for optimal activation of prekallikrein. The role of limited proteolysis in the activation of prekallikrein induced by dextran sulfate was studied by adding 125I-prekallikrein to plasma. The generation of kallikrein activity paralleled the proteolytic cleavage of prekallikrein as judged on SDS gels in the presence of reducing agents. The same cleavage fragments were observed as obtained by activation of purified prekallikrein by beta-factor-XIIa. Addition of 131I-HMW kininogen and 125I-factor XII or 131I-HMW kininogen and 125I-prekallikrein to normal plasma followed by activation with dextran sulfate and analysis on SDS gels indicated that the observed cleavage of prekallikrein and HMW kininogen is fast compared to the observed cleavage of factor XII, which is much slower and less extensive. During the first minutes of incubation of normal plasma with dextran sulfate, mainly alpha-factor-XIIa is formed. During prolonged incubation, beta-factor-XIIa is also formed.

Dextran Sulfate↗
PubMed1990

A model for the interplay of inflammatory mediators in sepsis--a study in 48 patients.

Previously we studied levels of the cytokine IL-6 and activation of the complement and contact system and of neutrophils in a group of 48 patients with sepsis. Some of these inflammatory parameters appeared to be associated with a poor prognosis. Here we report on the relationships of C4a and C3a (complement activation products), of factor XII and prekallikrein (contact system proteins), of elastase (a protease released by activated neutrophils) and of the cytokine IL-6 to hemodynamic and biochemical parameters measured in those 48 patients at the time of admission to the Intensive Care Unit. No significant correlations between any inflammatory parameter and either systemic vascular resistance or cardiac index were found. Mean arterial pressure significantly correlated with both factor XII and prekallikrein levels. Lactate correlated with C3a and C4a, with elastase, and in particular, with IL-6, whereas it did not correlate with either factor XII or prekallikrein. Platelet numbers inversely correlated with both C3a and C4a, as well as with elastase and IL-6, whereas they positively correlated with factor XII and prekallikrein. Based on these findings we propose a model for the interplay of these inflammatory mediators in the pathogenesis of sepsis. This model takes into consideration the occurrence of capillary leakage, shock, disseminated intravascular coagulation, thrombocytopenia and of acute phase reactions in sepsis.

Complement Activation↗
PubMed1977

Coagulation abnormalities in women taking oral contraceptives.

Thirteen asymptomatic women taking oral contraceptives (OCs) were compared with normal subjects. Platelet aggregation and serotonin (tagged with carbon 14) release with adenosine diphosphate, epinephrine, and collagen did not differ from controls. Activation of the intrinsic coagulation pathway was evaluated by measurements of factor XII, prekallikrein, and kallikrein inhibitors. Women taking OCs had normal factor XII levels, moderately elevated prekallikrein levels, and decreased kallikrein inhibitor levels, a pattern not consistent with activation of the intrinsic pathway. The concentration of heavy molecular weight fibrinogen derivatives (HMWFD) was significantly elevated (P less than .001). In contrast, fibrin and fibrinogen degradation products in serum were lower than normal (P less than .05). The increased HMWFD concentration may reflect activation of the coagulation system not mediated by factor XII activation nor potentiated by decreased antithrombin III. Thus, plasma coagulation abnormalities rather than platelet changes may be the factor that predisposes women taking OCs to thromboembolic disorders.

Adult↗