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PubMed1984

Defective intrinsic fibrinolytic activity in a patient with severe factor XII-deficiency and myocardial infarction.

The paper reports the occurrence of myocardial infarctions in a patient with severe deficiency of blood coagulation factor XII (Hageman factor). Factor XII plays a central role in the intrinsic activation of fibrinolysis and consequently the defective intrinsic fibrinolytic activity detected in the present case casts some doubt on its role in the increased vulnerability to thrombotic accident.

Adult↗
PubMed1984

The possible role of platelets in bypassing the contact phase of blood coagulation.

Data presented herein and previously support an active role for platelets in promoting the interaction and activation of the coagulation proteins of the contact phase of intrinsic coagulation. The platelet membrane, activated by ADP collagen or thrombin, can promote the proteolytic activation of factor XII to factor XIIa in the presence of kallikrein and high molecular weight kininogen. The zymogen factor XI associates with high molecular weight kininogen in plasma and becomes bound to a site on the membrane of thrombin or collagen activated platelets. Thereafter, platelet bound factor XI can be proteolytically activated to factor XIa either in the presence of factor XIIa or in the presence of kallikrein. These observations could explain the absence of bleeding complications in patients with factor XII deficiency. In addition, platelets contain a molecule which has a higher molecular weight than plasma factor XI and possibly consists of a tetramer of four identical subunits of 52000 daltons each of which is functionally and immunologically similar to plasma factor XI. Since this molecule is present in the platelets of patients with severe plasma factor XI deficiency and no evidence of bleeding, we postulate that platelet factor XI can substitute for plasma factor XI in hemostasis and possibly account for the considerable variability in clinical severity observed in patients with factor XI deficiency.

Blood Coagulation↗
PubMed1978

Deficiency of factor XII-dependent plasminogen proactivator in prekallikrein-deficient plasma.

Normal human plasma contains a factor XII (Hageman factor)-dependent plasminogen proactivator in its gamma globulin fraction. On the basis of both fibrin plate and clot lysis assays, this plasminogen proactivator activity was shown to be absent from the gamma globulin fraction of prekallikrein (Fletcher factor)-deficient plasma of two unrelated patients. This observation suggests that factor XII-dependent plasminogen proactivator is identical to plasma prekallikrein.

Blood Coagulation Disorders↗
PubMed1984

Intrinsic plasma fibrinolysis: involvement of urokinase-related activity in the factor XII-independent plasminogen proactivator pathway.

A portion of human blood fibrinolytic activity can be quenched by antibodies to urokinase. We attempted to identify this portion and its position in the three pathways (extrinsic, intrinsic factor XII dependent, and intrinsic factor XII independent) of plasminogen activator activity that have been defined in the DEFs of plasma. Activity quenching in various plasmas (including plasma adsorbed by agarose-bound AUK) demonstrated the involvement of a discrete activator activity of 40 to 50 BAU/ml with little variation among individuals (43 +/- 6 (SD) BAU/ml, n = 13). The quenching did not involve, quantitatively or qualitatively, the extrinsic (tissue-type) plasminogen activator activity varying between 1 and 146 BAU/ml in baseline plasma and in plasma obtained after stimulation by venous occlusion, exercise, or DDAVP administration. In confirmation, extrinsic activator activity was recovered in plasma adsorbed by agarose-bound AUK. The quenching also did not involve the factor XII-dependent activities; it was quantitatively normal in plasma with Hageman (n = 3) and Fletcher (n = 2) traits, and AUK did not interfere with the generation of factor XII-dependent fibrinolytic activity by addition of purified activated factor XII in plasma with Hageman trait. There was no effect of AUK on kallikrein generation, kallikrein activities, or the APPT, nor were these aspects altered in depleted plasma. In conclusion, the quenching involved the factor XII-independent system of intrinsic fibrinolysis. Addition of purified urinary urokinase did not result in restoration of missing activity in plasma adsorbed by AUK-agarose. The quenching, therefore, probably involved an apparent urokinase-related activator component in plasma.

Dextran Sulfate↗
PubMed2006

Platelets promote coagulation factor XII-mediated proteolytic cascade systems in plasma.

Blood coagulation factor XII (FXII, Hageman factor) is a plasma serine protease which is autoactivated following contact with negatively charged surfaces in a reaction involving plasma kallikrein and high-molecular-weight kininogen (contact phase activation). Active FXII has the ability to initiate blood clotting via the intrinsic pathway of coagulation and inflammatory reactions via the kallikrein-kinin system. Here we have determined FXII-mediated bradykinin formation and clotting in plasma. Western blotting analysis with specific antibodies against various parts of the contact factors revealed that limited activation of FXII is sufficient to promote plasma kallikrein activation, resulting in the conversion of high-molecular-weight kininogen and bradykinin generation. The presence of platelets significantly promoted FXII-initiated bradykinin formation. Similarly, in vitro clotting assays revealed that platelets critically promoted FXII-driven thrombin and fibrin formation. In summary, our data suggest that FXII-initiated protease cascades may proceed on platelet surfaces, with implications for inflammation and clotting.

Blood Coagulation↗
PubMed1984

Inhibition of the cold activation of Factor VII and the prothrombin time.

Normal whole blood, collected and stored in borosilicate or commercial siliconized borosilicate tubes at 4 degrees C, undergoes a time-dependent activation of Factor VII and a shortening of the prothrombin time (PT). Addition of inhibitors to Factor XII fragments (corn Hageman factor inhibitor, CHFI) or to activated Factor XII (Cytochrome-C) inhibited in a concentration-dependent way the cold-promoted activation of Factor VII and the shortening of the PT. When celite was added to whole blood in polypropylene tubes at 4 degrees C, Factor VII was activated and the PT shortened. Preincubation of celite with CHFI or Cytochrome-C prevented the activation of Factor XII and the subsequent activation of Factor VII and the PT. These studies demonstrate the importance of Factor XII in the cold activation of Factor VII and shortening of the PT and indicate that inhibitors to activated Factor XII or XII fragments are useful in inhibiting in vitro shortening of the PT. These findings suggest that the development of a collection tube that prevents contact activation also would inhibit adequately the cold-promoted activation of the PT and Factor VII.

Aprotinin↗
PubMed1984

Cleavage of human high molecular weight kininogen markedly enhances its coagulant activity. Evidence that this molecule exists as a procofactor.

High molecular weight kininogen (HMW)-kininogen, the cofactor of contact-activated blood coagulation, accelerates the activation of Factor XII, prekallikrein, and Factor XI on a negatively charged surface. Although prekallikrein and Factor XI circulate as a complex with HMW-kininogen, no physical association has been demonstrated between Factor XII and HMW-kininogen, nor has the order of adsorption to surfaces of these proteins been fully clarified. In this report we explore the requirements for adsorption of HMW-kininogen to a clot-promoting surface (kaolin), in purified systems, as well as in normal plasma and plasma genetically deficient in each of the proteins of the contact system. The fraction of each coagulant protein associated with the kaolin pellet was determined by measuring the difference in coagulant activity between the initial sample and supernatants after incubation with kaolin, or by directly quantifying the amount of 125I-HMW-kininogen that was associated with the kaolin pellet. In normal plasma, the adsorption of HMW-kininogen to kaolin increased as the quantity of kaolin was increased in the incubation mixture. However, the HMW-kininogen in Factor XII-deficient plasma did not absorb appreciably to kaolin. Furthermore, the quantity of HMW-kininogen from prekallikrein-deficient plasma that adsorbed to kaolin was decreased as compared with normal plasma. These observations suggested that HMW-kininogen in plasma must be altered by a reaction involving both Factor XII and prekallikrein in order for HMW-kininogen to adsorb to kaolin, and to express its coagulant activity. Subsequently, the consequence of the inability of HMW-kininogen to associate with a negatively charged surface results in decreased surface activation. This assessment was derived from the further observation of the lack of prekallikrein adsorption and the diminished Factor XI adsorption in both Factor XII-deficient and HMW-kininogen-deficient plasmas, since these two zymogens (prekallikrein and Factor XI) are transported to a negatively charged surface in complex with HMW-kininogen. The percentage of HMW-kininogen coagulant activity that adsorbed to kaolin closely correlated (r = 0.98, slope = 0.97) with the amount of 125I-HMW-kininogen adsorbed, suggesting that adsorption of HMW-kininogen results in the expression of its coagulant activity. Since kallikrein, which is known to cleave HMW-kininogen, is generated when kaolin is added to plasma, we tested the hypothesis that proteolysis by kallikrein was responsible for the enhanced adsorption of HMW-kininogen to kaolin. When purified HMW-kininogen was incubated with purified kallikrein, its ability to absorb to kaolin increased with time of digestion until a maximum was reached. Moreover, (125)I-HMW-kininogen, after cleavage by kallikrein, had markedly increased affinity for kaolin than the uncleaved starting material. Furthermore, fibrinogen, at plasma concentration (3 mg/ml), markedly curtailed the adsorption of a mixture of cleaved and uncleaved HMW-kininogen to kaolin, but was unable to prevent fully cleaved HMW-kininogen from adsorbing to the kaolin. Addition of purified kallikrein to Factor XII-deficient plasma, which bypasses Factor XII-dependent contact-activation amplified the ability of its HMW-kininogen to adsorb to kaolin. These observations indicate that HMW-kininogen is a procofactor that is activated by kallikrein, a product of a reaction which it accelerates. This cleavage, which enhances its association with a clot-promoting surface in a plasma environment, is an event that is necessary for expression of its cofactor activity. These interactions would allow coordination of HMW-kininogen adsorption with the adsorption of Factor XII, which adsorbs independently of cleavage, to the same negatively charged surface.

Adsorption↗
PubMed2003

Coagulation activators and inhibitors in the neointima of polyester vascular grafts.

The surface of synthetic vascular grafts is thrombogenic, which implies a risk for their occlusion. The aim of the study was to evaluate expression of coagulation components in the polyester vascular grafts neointima. The study was carried out on 18 dogs, which underwent replacement of the abdominal aorta with a polyester prosthesis. Grafts were removed after 1, 4 and 12 months. Immunohistochemical labeling for von Willebrand factor, tissue factor, factor XII, tissue factor pathway inhibitor, thrombomodulin, protein C, protein S and prothrombin activation fragment F1 + 2 was performed. Increasing intensity of von Willebrand factor expression was found in successive periods of the study. Factor XII was shown in the whole neointima after 1 month, whereas in the following periods its presence was limited to the luminal surface. Tissue factor expression was demonstrated after 1 month and its intensity increased in later periods. Tissue factor pathway inhibitor and thrombomodulin expression was demonstrated after 4 and 12 months. Protein C and protein S were present in all observation periods, as well as prothrombin activation fragment F1 + 2. Results indicate a high thrombotic potential of the graft neointima early after prosthesis implantation, whereas in the late postoperative follow-up increasing expression of coagulation inhibitors reduces thrombotic properties of the graft neointima.

Animals↗
PubMed1990

Activation of coagulation after administration of tumor necrosis factor to normal subjects.

Tumor necrosis factor has been implicated in the activation of blood coagulation in septicemia, a condition commonly associated with intravascular coagulation and disturbances of hemostasis. To evaluate the early dynamics and the route of the in vivo coagulative response to tumor necrosis factor, we performed a controlled study in six healthy men, monitoring the activation of the common and intrinsic pathways of coagulation with highly sensitive and specific radioimmunoassays. Recombinant human tumor necrosis factor, administered as an intravenous bolus injection (50 micrograms per square meter of body-surface area), induced an early and short-lived rise in circulating levels of the activation peptide of factor X, reaching maximal values after 30 to 45 minutes (mean +/- SEM increase after 45 minutes, 34.2 +/- 18.2 percent; tumor necrosis factor vs. saline, P = 0.015). This was followed by a gradual and prolonged increase in the plasma concentration of the prothrombin fragment F1+2, peaking after four to five hours (mean increase after five hours, 348.0 +/- 144.8 percent; tumor necrosis factor vs. saline, P less than 0.0001). These findings signify the formation of factor Xa (activated factor X) and the activation of prothrombin. Activation of the intrinsic pathway could not be detected by a series of measurements of the plasma levels of factor XII, prekallikrein, factor XIIa-C1 inhibitor complexes, kallikrein-C1 inhibitor complexes, and the activation peptide of factor IX. The delay between the maximal activation of factor X and that of prothrombin amounted to several hours, indicating that neutralization of factor Xa activity was slow. We conclude that a single injection of tumor necrosis factor elicits a rapid and sustained activation of the common pathway of coagulation, probably induced through the extrinsic route. Our results suggest that tumor necrosis factor could play an important part in the early activation of the hemostatic mechanism in septicemia.

Adult↗
PubMed1979

Human high molecular weight kininogen. Studies of structure-function relationships and of proteolysis of the molecule occurring during contact activation of plasma.

Human high Mr kininogen was purified from normal plasma in 35% yield. The purified high Mr kininogen appeared homogeneous on polyacrylamide gels in the presence of sodium dodecyl sulfate and mercaptoethanol and gave a single protein band with an apparent Mr = 110,000. Using sedimentation equilibrium techniques, the observed Mr was 108,000 +/- 2,000. Human plasma kallikrein cleaves high Mr kininogen to liberate kinin and give a kinin-free, two-chain, disulfide-linked molecule containing a heavy chain of apparent Mr = 65,000 and a light chain of apparent Mr = 44,000. The light chain is histidine-rich and exhibits a high affinity for negatively charged materials. The isolated alkylated light chain quantitatively retains the procoagulant activity of the single-chain parent molecule. 125I-Human high Mr kininogen undergoes cleavage in plasma during contact activation initiated by addition of kaolin. This cleavage, which liberates kinin and gives a two-chain, disulfide-linked molecule, is dependent upon the presence of prekallikrein and Factor XII (Hageman factor) in plasma. Addition of purified plasma kallikrein to normal plasma or to plasmas deficient in prekallikrein or Factor XII in the presence or absence of kaolin results in cleavage of high Mr kininogen and kinin formation.

Amino Acids↗
PubMed1985

Amino acid sequence of the heavy chain of human alpha-factor XIIa (activated Hageman factor).

The amino acid sequence of the heavy chain of human alpha-factor XIIa (activated Hageman factor) was determined by automated Edman degradation using the peptides produced by chemical and enzymatic cleavages of intact factor XII and alpha-factor XIIa. Combining this sequence with the previously determined sequence of beta-factor XIIa (Fujikawa, K., and McMullen, B. A. (1983) J. Biol. Chem. 258, 10924-10933), the complete amino acid sequence of human factor XII has been established. The heavy chain of alpha-factor XIIa is composed of 353 amino acid residues containing one Asn-linked and six probable O-linked carbohydrate chains. The heavy chain of alpha-factor XIIa appears to contain four different domains including a "kringle," a "growth factor" domain, and the "type I" and "type II" domains of fibronectin. The domain organization of factor XII is analogous to those of several fibrinolytic proteins, including tissue plasminogen activator and urokinase, suggesting that factor XII belongs to the same protease subfamily as these two proteins.

Amino Acid Sequence↗
PubMed2001

Factor XII-dependent contact activation on endothelial cells and binding proteins gC1qR and cytokeratin 1.

Although proteins of the kinin-forming pathway are bound along the surface of endothelial cells, the mechanism of activation of this proteolytic cascade is unclear. Endothelial cell surface proteins, gC1qR and cytokeratin 1, are capable of binding Factor XII and high molecular weight kininogen (HK) in a zinc-dependent reaction thus we considered the possibility that these proteins might catalyze initiation of the cascade. Incubation of Factor XII, prekallikrein, and HK with gC1qR or cytokeratin 1 leads to a zinc-dependent and Factor XII-dependent conversion of prekallikrein to kallikrein. We also demonstrate that normal plasma is capable of activating upon interaction with the cells whereas plasma deficient in Factor XII, prekallikrein and HK do not activate. Normal plasma activation was inhibitable by antibody to gC1qR and cytokeratin 1. Thus, gC1qR and cytokeratin 1, represent potential initiating surfaces for activation of the plasma kinin-forming cascade and may do so as a result of their expression along cell surfaces.

Carrier Proteins↗
PubMed1995

Prognostic value of assessing contact system activation and factor V in systemic inflammatory response syndrome.

OBJECTIVE: To test if serially sampled determinations of the contact system proteins and factor V have prognostic value for death in patients who develop the systemic inflammatory response syndrome. DESIGN: Prospective, observational study with sequential measurements in an inception cohort. SETTING: Medical intensive care unit (ICU) in a community hospital. PATIENTS: Over a 1-yr period, a population base sample of 23 patients was selected from all ICU admissions who met established criteria for the systemic inflammatory response syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Components of the contact system, factor XII, prekallikrein, high-molecular-weight kininogen, factor XI, alpha 2-macroglobulin-kallikrein complexes and factor V values were measured in plasma samples collected serially (day of admission, and at 2, 12, 24, 48 and/or 72 hrs or at discharge). Data were analyzed to determine if admission values or serially obtained values within 48 hrs were useful in predicting outcome. Fourteen patients survived and nine died. At admission, in all patients, assay values indicated that prekallikrein, high-molecular-weight kininogen, and factor V were significantly lower than normal (as observed in a range of 20 to 23 healthy adults), alpha 2-macroglobulin-kallikrein complexes were higher than normal, while concentrations of factor XII and factor XI were in the normal range. No differences were detected in the admission values between survivors and nonsurvivors, nor between patients with positive or negative blood cultures. However, subsequent values demonstrated a difference in values between survivors and nonsurvivors. Survivors showed improvement in high molecular weight kininogen values and higher than normal factor V values, as compared with nonsurvivors. CONCLUSIONS: Low or persistently low serial factor XII, high-molecular-weight kininogen and factor V values are associated with a poor prognosis, whereas high or increasing values of factor XII, high-molecular-weight kininogen, prekallikrein, and factor V all correlate with a favorable outcome.

Aged↗
PubMed1983

Enzymological aspects of blood coagulation.

Recent studies on the mechanism of initiation and regulation of blood coagulation are reviewed. In the intrinsic blood coagulation pathway, factor XII, prekallikrein (or factor XI) and high molecular weight kininogen from a complex on an anionic surface, such as exposed subendothelium at the site of vascular trauma. In complex, zymogen factor XII activates prekallikrein (or factor XI) by limited proteolysis to initiate the coagulation cascade. A similar initiating mechanism may be operative in the extrinsic pathway, where zymogen factor VII, complexed with a lipoprotein (tissue factor) and calcium ions, converts factor X to factor Xa. Factor Xa converts prothrombin to thrombin which converts soluble fibrinogen to an insoluble fibrin network which physically arrests the flow of blood from the damaged vasculature. In addition, thrombin converts protein C to activated protein C. Activated protein C functions as a negative regulator in the coagulation process by degrading factor VIIIa and factor Va.

Blood Coagulation↗
PubMed2006

Plasma levels of bradykinin are suppressed in factor XII-deficient mice.

A genetically-transmissible factor (F) XII-inactivated allele has been produced in mice by targeted replacement of exons 3-8 of the FXII gene with the neomycin resistance gene. Interbreeding of these mice provided offspring homozygous for two inactivated FXII alleles (FXII(-/-)). Male and female FXII-deficient mice bred normally in all genotypic combinations of the heterozygous and homozygous states, and the offspring survived to adulthood, suggesting that a total FXII deficiency does not affect embryonic development and survival. Neither FXII transcripts nor FXII antigen was found in various tissues of adult FXII(-/-) mice. No obvious unchallenged coagulopathies were present in FXII(-/-) adult mice, despite greatly prolonged activated partial thromboplastin times in this mouse cohort. FXII(-/-) mice were then used to assess the in vivo importance of the plasma FXII/prekallikrein/kininogen pathway in provision of resting plasma bradykinin (BK) levels and in generation of plasma BK stimulated by contact with an artificial surface, using a new and greatly improved plasma BK assay developed during these studies. It was found that approximately 50% of resting BK, and all of the contact-stimulated plasma BK, was provided by this FXII-dependent pathway, without a requirement for FXI. These results provide clear evidence that surface-stimulated BK production, in mice, is dependent on the activation of FXII.

Animals↗
PubMed1982

Adult nephrotic syndrome and acquired coagulopathies: Hageman factor deficiency.

Analysis of tests of coagulation and fibrinolysis from 20 adult nephrotics prior to the onset of therapy disclosed that 40 percent had low factor XII levels. The mean factor XI was normal. The platelet count and fibrinogen concentration were elevated. The findings of this study on adults are similar to those of Honig and Lindley(21) in the nephrotic syndrome of childhood. Subjects with minimal change disease constituted a small (15 percent) but readily segregated subpopulation without evidence of fibrinolysis in association with low factor XII activity. Prolongation of the activated partial thromboplastin time corresponded in every instance with factor XII activities of ≤30 percent. Lengthening of the one stage prothrombin time was not directly attributable to factor deficiencies.

Adult↗
PubMed1981

Platelet-coagulant protein interactions in contact activation.

Previous studies have suggested that human platelets can promote the activation of factor XI by two different mechanisms, one requiring factor XII and ADP-treated platelets and the other requiring collagen-treated platelets in the apparent absence of factor XII. To investigate these hypotheses, isolated platelets were tested for their capacity to promote the activation and cleavage of purified factors XII and XI in various mixtures of purified factor XII, kallikrein, high molecular weight kininogen, and factor XI. That ADP- or collagen-treated platelets can promote the proteolytic activation of factor XII in mixtures containing kallikrein and HMW kininogen was shown by (1) the proteolytic cleavage of factor XII, (2) the development of factor XIIa coagulant activity, and (3) the proteolytic cleavage of 125I-labeled factor XII. Platelets treated with collagen or thrombin were shown to both coagulant assays and cleavage studies to participate with HMW kininogen and kallikrein in the proteolytic activation of factor XI by mechanisms that are partially dependent upon and partially independent of factor XII. These studies demonstrate that platelets can promote the proteolytic activation of factor XII by kallikrein and of factor XI by both factor XII-dependent and factor XII-independent mechanisms.

Adenosine Diphosphate↗
PubMed1962

The contact phase of coagulation in the presence of heparin.

The effect of heparin on the contact phase of coagulation has been investigated by a technique utilizing a solution of toluidine blue in calcium chloride. Heparin in a concentration of 7 units/ml. of plasma does not inhibit contact activation by glass. It is suggested that heparin does not prevent the activation of factor XII (Hageman factor) by glass or the subsequent formation of active factor XI (plasma thromboplastin antecedent).

Blood Coagulation↗