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PubMed1994

The corn inhibitor of blood coagulation factor XIIa. Crystallization and preliminary crystallographic analysis.

A 13.6 kDa protein from corn seeds is known to be a highly selective inhibitor of human blood coagulation Factor XIIa (or activated Hageman factor). We have crystallized this inhibitor at 23 degrees C and pH 7.5 from a solution of 30% polyethylene glycol 400, 0.2 M MgCl2, and 0.1 M Hepes. The crystals diffract to at least 2.1 A resolution. The space group is P4(2)2(1)2 with a = b = 57.15 A and c = 80.5 A. The crystals contain 51% solvent. Two heavy atom derivatives have been identified.

Cloning, Molecular↗
PubMed2000

Factor XIIa and triacylglycerol rich lipoproteins: responses to exercise intervention.

OBJECTIVES: (a) To determine if factor XIIa (FXIIa) would be sensitive to change from exercise intervention in a group of previously sedentary/low active middle aged men and women; (b) to investigate further the previously reported relation between FXIIa and triacylglycerol (TAG) rich lipoproteins. METHODS: Thirty seven men (mean (SD) age 57 (7) years) and 60 women (mean age 54 (7) years) completed the study. Before the intervention, these subjects were randomly allocated to a group of walkers (n = 81) or controls (n = 16). Before and after an 18 week walking intervention, fasted blood samples were collected and analysed for FXIIa, TAG, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and apolipoprotein (apo) B. RESULTS: Kruskal-Wallis analysis of data obtained before the intervention showed no significant differences (p>0.4) between the walking and control groups for age, height, body mass, gender, FXIIa, TAG, TC, HDL-C, or apo B, although the women did show significantly lower levels of TAG (p<0.04) and higher HDL-C (p<0.0001) than the men. General linear model analysis of data obtained after the intervention, using the baseline value as a covariate, showed significant reductions (p<0.0001) in FXIIa for the walkers compared with the controls. Pearson product-moment correlations also showed significant relations between the concentrations of FXIIa and TAG, TC, LDL-C, and apo B. CONCLUSIONS: The findings of this study suggest that FXIIa is sensitive to change from exercise intervention and support previous research showing an association between the concentrations of FXIIa and TAG rich lipoproteins.

Cholesterol, HDL↗
PubMed2000

In vivo bypass of hemophilia A coagulation defect by factor XIIa implant.

Hemophilia A and B coagulation defects, which are caused by deficiencies of Factor VIII and Factor IX, respectively, can be bypassed by administration of recombinant Factor VIIa. However, the short half-life of recombinant Factor VIIa in vivo negates its routine clinical use. We report here an in vivo method for the continuous generation of Factor VIIa. The method depends on the implantation of a porous chamber that contains Factor Xa or XIIa, and continuously generates Factor VIIa bypass activity from the subject's own Factor VII, which enters the chamber by diffusion. Once inside, the Factor VII is cleaved to Factor VIIa by the immobilized Factor Xa or XIIa. The newly created Factor VIIa diffuses out of the chamber and back into the circulation, where it can bypass the deficient Factors VIII or IX, and enable coagulation to occur. In vitro, this method generates sufficient Factor VIIa to substantially correct Factor VIII-deficient plasma when assessed by the classical aPTT coagulation assay. In vivo, a Factor XIIa peritoneal implant generates bypass activity for up to one month when tested in rhesus monkeys. Implantation of such a chamber in a patient with hemophilia A or B could eventually provide a viable alternative to replacement therapies using exogenous coagulation factors.

Animals↗
PubMed1990

Cabbage seed protease inhibitor: a slow, tight-binding inhibitor of trypsin with activity toward thrombin, activated Stuart factor (factor Xa), activated Hageman factor (factor XIIa), and plasmin.

An inhibitor of procoagulant and fibrinolytic enzymes was derived from cabbage seeds by a procedure using acetone precipitation, ion-exchange chromatography, and gel filtration. The cabbage seed inhibitor was a 10-Kd monomeric protein with intrachain disulfide bonds. This preparation prevented clot formation in whole blood and blocked the ability of thrombin to induce clot formation in plasma and to induce platelet aggregation. A number of proteases were inhibited, as demonstrated by using purified enzymes in amidolytic assays. Tight-binding inhibition was observed for activated Stuart factor (factor Xa) and plasmin. Inhibition of thrombin and activated Hageman factor (factor XIIa) was observed with a molar excess of inhibitor. No inhibition was detected for activated plasma thromboplastin antecedent (factor XIa), plasma kallikrein, or C1 esterase. Reaction progress curves for trypsin indicated slow, tight-binding inhibition, with an apparent inhibition constant in the nanomolar range or less. The electrophoretic mobility of trypsin was altered by the inhibitor in nondenaturing polyacrylamide gel electrophoresis (PAGE) but not in sodium dodecyl sulfate (SDS)-PAGE, indicating noncovalent bonding. Only partial reversal of trypsin inhibition could be demonstrated by washing the inhibitor from enzyme immobilized on solid beads. A dot-blot technique with cabbage seed inhibitor was capable of detecting 10 ng nitrocellulose-bound trypsin. The dot-blot technique also appeared capable of detecting plasmin. These findings demonstrated the potential utility of this inhibitor as a probe for detection of tightly bound proteases. In summary, cabbage seed extracts contain an inhibitor with activity toward a broad range of proteases important to hemostasis. To our knowledge, this agent represents the first inhibitor isolated from a plant source that inhibits thrombin.

Brassica↗
PubMed1977

Demonstration and mode of action of an inhibitor for activated Hageman factor (factor XIIa) of the intrinsic blood coagulation pathway from Schistosoma mansoni.

An anticoagulant activity from adult Schistosoma mansoni whole worm homogenate is described. The inhibitor appears to be specific for the contact activation step of the intrinsic pathway. Experiments with both human and mouse plasmas have defined the specificity of the inhibitor as follows: (1) It lengthens the partial thromboplastin time of normal plasma. (2) It has no effect on the prothombin time and Russell's viper venom time of normal plasma. (3) Preactivation of normal plasma by a contact activator such as Celite eliminates essentially all inhibitory activity. (4) The inhibitor appears to be heat stable and can be precipitated by centrifugation above 27,000 g. (5) The inhibitor has no effect on the activation of factor XII by Celite. (6) The activation of factor XI by factor XIIa, however, is inhibited by the schistosomal inhibitor. The above data are consistent with the view that S. mansoni adults possess an anticoagulant that is capable of specifically inhibiting the conversion of factor XI to factor XIa by factor XIIa.

Animals↗
PubMed1995

Ecotin is a potent inhibitor of the contact system proteases factor XIIa and plasma kallikrein.

Ecotin, a serine protease inhibitor found in the periplasm of Escherichia coli, has been characterized as a potent reversible tight-binding inhibitor of the human contact activation proteases factor XIIa (FXIIa) and plasma kallikrein, having Ki values of 89 pM and 163 pM, respectively. Ecotin also inhibited human leukocyte elastase (HLE) with high affinity (Ki = 55 pM). The association rate constants kon for FXIIa and kallikrein were 5.3 x 10(5) M-1.s-1 and 2.9 x 10(5) M-1.s-1, respectively. The dissociation rate constant koff for kallikrein, measured in the presence of HLE to prevent reassociation, was 6.3 x 10(-5) s-1; the koff for ecotin with FXIIa was 4.7 x 10(-5) s-1. Both FXIIa and kallikrein cleaved ecotin slowly at pH 5.0, identifying Met-84 as the P1 residue. The potent anticoagulant effect by ecotin is explained by the coincident inhibition of FXIIa, kallikrein, and FXa and suggests that it may be useful in the study of inflammatory or thrombotic disorders such as sepsis or cardiopulmonary bypass.

Amino Acid Sequence↗
PubMed1999

The levels of factor XIIa generated in human plasma on an electronegative surface are insensitive to wide variation in the concentration of FXII, prekallikrein, high molecular weight kininogen or FXI.

The contribution of the various components of the contact system in the generation of factor XIIa (FXIIa) and of kallikrein (KRN) on an electronegative surface and the release of the generated enzymes to the bulk phase was examined in mixtures of normal human plasma and plasmas congenitally deficient in these components. The incubation of normal human plasma in the presence of sulphatide vesicles (40 microM) resulted in a fast generation of amidolytic activities due to FXIIa and to KRN followed by slower first-order inactivation rates of FXIIa (k'FXIIa) and of KRN (k'KRN) due to the presence of esterase inhibitors. Variation of the levels of factor XII (FXII), over a wide range, showed little effect on levels of FXIIa and of KRN but no activities were detected in 100% FXII-deficient plasma. The variation of prekallikrein (PKRN) concentration showed little effect on the generation of FXIIa but the generation of KRN declined linearly with the decrease in the level of PKRN. No activities were detected on treatment of PKRN-deficient plasma. The variation in the concentration of high molecular weight kininogen (HK) showed effects on FXIIa and KRN that were qualitatively similar to those seen on variation of PKRN but 100% HK-deficient plasma generated considerable activities of both FXIIa and KRN. The variation in the concentration of factor XI (FXI) showed no effect on the generation of FXIIa, whereas KRN levels increased linearly with the contribution of FXI-deficient in normal plasma. The present results suggest that the contiguous binding of FXIIa, FXII, PKRN-HK and FXI-HK onto the electronegative surface induces a rapid generation of FXIIa and KRN. The bound PKRN-HK complex prevents the release of generated FXIIa and therefore further binding and activation of FXII from the bulk phase. Consequently, the turnover of FXII is independent of its levels in the bulk phase and is rather related to the concentration of contact surface. The generated KRN is also protected by HK. However, since the enzyme responsible for the activation of PKRN-HK is FXIIa, the levels of generated KRN are positively related to the concentration of substrate.

Animals↗
PubMed2004

A proteinase inhibitor from Caesalpinia echinata (pau-brasil) seeds for plasma kallikrein, plasmin and factor XIIa.

Caesalpinia echinata is a tree belonging to the Leguminosae family. The red color of the trunk, looking like burning wood ('brasa' in Portuguese), is the origin of the name Brazil. Seeds of leguminous plants contain high amounts of serine proteinase inhibitors that can affect different biological processes. Here we show that a protein isolated from seeds of C. echinata is able to inhibit enzymes that participate in blood coagulation and fibrinolysis. This inhibitor (CeKI) was purified to homogeneity by ion exchange and reversed-phase chromatography. SDS-PAGE indicated a single polypeptide chain with a molecular mass of 20 kDa. CeKI inhibits human plasma kallikrein ( K i =3.1 nM), plasmin ( K i =0.18 nM), factor XIIa ( K i =0.18 nM), trypsin ( K i =21.5 nM) and factor Xa ( K i =0.49 mM). CeKI inhibited kinin release from highmolecular- mass kininogen by kallikrein in vitro . The N-terminal sequence, determined by automatic Edman degradation, identified the inhibitor as a member of the Kunitz family. The secondary structure, determined by circular dichroism, is mainly a random coil followed by beta-sheet structure. The action of CeKI on enzymes of the blood-clotting intrinsic pathway was confirmed by prolongation of the activated partial thromboplastin time.

Amino Acid Sequence↗
PubMed1998

The effect of two different 18-week walking programmes on aerobic fitness, selected blood lipids and factor XIIa.

Forty-nine previously sedentary or low active individuals aged 40-71 years were allocated to three groups. The long walking group participated in an 18-week walking programme which consisted of walks lasting 20-40 min; the repetitive short walking group completed walks of between 10 and 15 min, up to three times a day, with no less than 120 min between each walk; and the control group maintained their low level of activity. Both walking programmes began at a prescribed 60 min x week(-1), which increased steadily up to 200 min x week(-1) by week 12. During the study, the long walking group walked for an estimated 2514 min (139 min x week(-1)), expending an estimated 67.5 MJ (3.72 MJ x week(-1)) at an estimated 73% of their age-predicted maximum heart rate and 68% of their estimated VO2max. The repetitive short walking group walked for an estimated 2476 min (135 min x week(-1)), expending an estimated 58.5 MJ (3.17 MJ x week(-1)) at an estimated 71% of their age-predicted maximum heart rate and 65% of their estimated VO2max. The results showed a statistically significant reduction in heart rate during a standardized step test (pre- vs post-intervention) in both walking groups, indicating an improvement in aerobic fitness, although the control group showed a higher average heart rate during the post-intervention test, indicating reduced fitness. When compared with the male subjects pre-intervention, the females possessed more favourable levels of high-density lipoprotein (HDL) cholesterol (P< 0.001), apolipoprotein (apo) AI (P < 0.001) and ratios of total cholesterol:HDL cholesterol (P< 0.02) and low-density lipoprotein (LDL) cholesterol: HDL cholesterol (P< 0.02). Compared with the controls post-intervention, the walking groups showed no statistically significant changes in total cholesterol, LDL cholesterol, HDL cholesterol, apo AI, apo AII, apo B, or the ratios of total cholesterol: HDL cholesterol, LDL cholesterol: HDL cholesterol, apo AI: apo B or apo AI: apo AII (P > 0.05). Relative to the walking groups, factor XIIa increased in the control group (P < 0.05). We conclude that, although both walking programmes appeared to improve aerobic fitness, there was no evidence of improvements in the blood lipids or associated apolipoproteins of the walking groups. Further analysis indicated that this apparent lack of change may have been related to the subjects' relatively good pre-intervention blood lipid profiles, which restricted the potential for change. The implications of the observed changes in the coagulation/fibrinolytic factors remain unclear.

Adult↗
PubMed1981

The molecular-weight dependence of the rate-enhancing effect of heparin on the inhibition of thrombin, factor Xa, factor IXa, factor XIa, factor XIIa and kallikrein by antithrombin.

Heparin fractions of different molecular weight and with high affinity for antithrombin were studied with respect to their ability to potentiate the inhibition of activated clotting factors by antithrombin. Inhibition of thrombin, Factor IXa and Factor XIa showed similarities in the dependence on the molecular weight of heparin and was found to decrease with decreasing molecular weight. Inactivation of Factor Xa, Factor XIIa and kallikrein was, however, less dependent on the size of the polysaccharide and, to a great extent, was potentiated even by low-molecular-weight heparin fractions that had virtually no effect on the inhibition of thrombin, Factor IXa and Factor XIa.

Antithrombin III↗
PubMed1983

[Prothrombin--substrate for blood plasma kallikrein and factor XIIa].

A study was made of the interaction between prothrombin and enzymes: blood plasma kallikrein and factors alpha-XIIa and beta-XIIa immobilized on enzacryl-AH. Kallikrein-induced prothrombin proteolysis was accompanied by a decrease in prothrombin activity, appearance of BAME-esterase and poor clotting activity. As a result of fractionation of products on the column with DEAE-Sephadex A-50, some fractions that have thrombin amidase activity (splitting of the substrate S-2238) and high antithrombin activity were obtained. Antithrombin activity manifested in the inhibition of fibrinmonomer aggregation during fibrin formation. During incubation with prothrombin, factors alpha-XIIa and beta-XIIa also stimulated the appearance of BAME-esterase activity. None of the immobilized enzymes activated factor X.

Acrylic Resins↗
PubMed1990

Interactions of C1(-)-inhibitors from normal persons and patients with type II hereditary angioneurotic edema with purified activated Hageman factor (factor XIIa).

Activated high molecular weight Hageman factor (75 Kd) and Hageman factor carboxy-terminal fragments both formed complexes with purified C1(-)-inhibitor, but the Hageman factor fragments appeared to have a higher affinity for the C1(-)-inhibitor than activated Hageman factor. Therefore, the clot-promoting activity of activated Hageman factor might be relatively unimpaired if Hageman factor fragments are also present. Normal C1(-)-inhibitor was cleaved by Hageman factor fragments. Clot-promoting activity was not generated in Hageman factor by exposure to Hageman factor fragments, nor was Hageman factor cleaved by Hageman factor fragments. When Hageman factor was cleaved by streptokinase-activated plasminogen, a 40 Kd fragment was released. In contrast to their interactions with other proteinases, which are blocked by normal C1(-)-inhibitor, Type II C1(-)-inhibitors from plasmas of affected members of eight different kindred with this form of hereditary angioneurotic edema all inhibited the specific coagulant activity of activated Hageman factor to some degree. They did not all form complexes with activated Hageman factor that were stable during sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

Angioedema↗
PubMed1998

The association of factor VIIa, factor XIIa and beta2-glycoprotein-1 with triglyceride-rich lipoproteins in normolipidaemic subjects.

The activation of factors XII (FXII) and VII (FVII) has been shown to occur on the surface of lipoproteins in the presence of lipoprotein lipase and may be modulated by beta2glycoprotein-1 (beta2GP1). In the postprandial state FVII is activated without apparent activation of FXII in plasma. We investigated whether beta2GP1, FXIIa and FVIIa are associated with triglyceride-rich lipoproteins in the fasting and postprandial state. Six normal subjects were studied while fasting and 1, 2 and 4 h after ingestion of 100 g fat. We confirmed that plasma FVIIa activity, but not FXIIa antigen, was increased in the postprandial period. FXIIa, FVIIa and beta2GP1 were associated with chylomicra-rich lipoproteins, and lipase or Triton X-100 treatment caused an increase in FXIIa in plasma and chylomicra without an increase in FVIIa. This suggests that FXIIa may be formed in the postprandial period, but its antigenic determinants are masked by the association with lipoprotein particles, although it could still express proteolytic activity. Alternatively a FXII-independent mechanism or surface other than triglyceride-rich lipoproteins may be responsible for FVII activation in the postprandial state.

Chylomicrons↗
PubMed1977

Labeling of a major fibroblast surface protein (fibronectin) catalyzed by blood coagulation factor XIIa.

Incubation of cultured human fibroblasts with blood coagulation factor XIIIa (plasma transglutaminase, fibrinoligase) and the fluorescent primary amine, N-(5-aminopentyl)-5-dimethylaminonaphthalene-1-sulfonamide, resulted in fluorescent labeling of three cellular polypeptides. The molecular weights of the labeled polypeptides, estimated by polyacrylamide gel electrophoresis in sodium dodecyl sulfate after reduction, were: greater than 1.2-10(6), 2.2-10(5), and 1.3-10(5). The labeled 2.2-10(5) dalton polypeptide was susceptible to mild trypsinization and not present in cultures of SV-40 transformed fibroblasts, indicating that it is the subunit of cell-surface fibronectin and identical with the external transformation-sensitive polypeptide of similar molecular weight described by others. Upon coelectrophoresis, the labeled 2.2-10(5) dalton polypeptide migrated slightly behind the subunit of plasma fibronectin (cold-insoluble globulin), indicating that the immunologically cross-reactive forms of fibronectin in human plasma and cultured human fibroblasts differ slightly in molecular weight. The identities of the labeled greater than 1.2-10(6) and 1.3-10(5) dalton polypeptides are not known. The XIIa-reactive glutamine residues of fibroblast cell-surface proteins are potential sites for intermolecular cross-linking (by xi-(gamma-glutamyl)lysyl linkages) to other proteins of connective tissue.

Binding Sites↗
PubMed2005

A novel anticoagulant purified from fish protein hydrolysate inhibits factor XIIa and platelet aggregation.

A novel fish protein having anticoagulant and antiplatelet properties was enzymatically extracted from the marine fish, yellowfin sole (Limanda aspera) and purified to homogeneity producing an overall purification fold of 206.6. MALDI-TOF mass spectroscopic and SDS-PAGE analysis identified the purified protein as 12.01 kDa single-chain monomeric protein. It inhibited the activated coagulation factor XII (FXIIa) by forming an inactive complex regardless of Zn2+ mediation, and was named, yellowfin sole anticoagulant protein (YAP). In addition, YAP act to antagonize platelet membrane glycoprotein integrin, to arrest platelet aggregation. However, YAP was not able to block the adhesion of platelets to collagen, which mediate via major collagen receptors, GPIa/IIa on platelet membrane. Furthermore, YAP did not possess plasminogen activator-like activity to activate fibrinolysis. In fact, our findings indicate that YAP binds with FXIIa and platelet membrane integrins to inhibit thrombosis in vitro.

Animals↗