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PubMed1990

Functional correlation between kallikrein and factor XII activated in human plasma.

Plasma kallikrein and FXIIa were assayed in acetone-treated human citrated plasma (CPLa) with the chromogenic peptide Bz-Ile-Glu-Gly-Arg-pNA (S-2222) as substrate. In end point assays with short incubation periods (1-10 min.) nearly all kallikrein present could be blocked by a low concentration of soybean trypsin inhibitor (STI). In 30 min. assays the main part of the kallikrein was recovered in a functional state not inhibited by STI, and at the same time the level of FXIIa (as amidase activity blocked by corn inhibitor, C.I.) was reduced to about 2/3 of the initial value. The formation of an association between FXIIa and kallikrein is suggested. In fractions from gel filtration of CPLa kallikrein was assayed as S-2302 amidase, high molecular weight kininogen (HK) was measured in rocket immunoassays, and HK and FXII were studied in PAGE immunoblot experiments. Kallikrein appeared as one peak together with HK (gel mol. wt. 300 KD), about 40% of HK was free (220 KD), and no FXII was observed in the kallikrein or HK peaks, but in two areas corresponding to 78-79 KD and 39-42 KD. When experiments, however, were carried out with plasma acetone-activated and gel filtered in the presence of benzamidine (5 mM), part of the amidase activity present in kallikrein peak fractions was blocked by C.I. This observation supports the above suggestion of an association between FXIIa and kallikrein.

Adult↗
PubMed2003

Severe prekallikrein (Fletcher factor) deficiency due to a compound heterozygosis (383Trp stop codon and Cys529Tyr).

We investigated a family with prekallikrein deficiency, using both standard coagulation tests and molecular biology techniques. The propositus was found to be a compound heterozygote for a Trp383 stop codon and a Cys529Tyr point mutation. The former mutation was located in exon 11, the latter in exon 14. The propositus inherited the first defect from his father and the second from his mother. Both parents had slightly low prekallikrein levels, but the combination of the two genetic defects produced a phenotype characterized by an extremely low prekallikrein activity and antigen. The propositus' plasma showed a progressive reduction in APTT when incubated for a long time. Conversely, plasma deficient in factor XII, factor XI or high molecular weight kininogen (HMWK) failed to show shortening of the APTT. No circulating anticoagulant was found because the patient's APTT was fully corrected by pooled nor-mal and factor XII-, factor XI- or HMWK deficient plasma. No associated abnormality was apparent in the propositus or his parents. As expected, no tendency for bleeding was noted even after tonsillectomy.

Adolescent↗
PubMed1991

Mechanism of the participation of the contact system in the Vroman effect. Review and summary.

The contact system comprises three zymogens (factor XII, factor XI, and prekallikrein) and the non-enzymatic activation cofactor, high-molecular-weight kininogen (HK). When blood comes into contact with negatively charged surfaces, a small amount of factor XII is adsorbed and activated which, in turn, generates kallikrein from prekallikrein. Kallikrein amplifies the activation of the contact system by producing additional factor XIIa molecules as well as by activating the cofactor, HK, to HKa. HKa, while complexed with either prekallikrein or factor XI, can penetrate a barrier of fibrinogen and adsorb to the surface, where it optimally positions these zymogens for activation by adjacent factor XIIa molecules. Factor XIa can then degrade the light chain of HKa, producing the inactive cofactor HKi, which no longer has the ability to adsorb to a surface or support coagulation. The Vroman effect refers to the 'conversion' of fibrinogen from plasma on a negatively charged surface. Fibrinogen is detectable within seconds after normal plasma contacts the surface but, within minutes, is undetectable. On the other hand, HK, although not initially detectable on the surface, is found at later times when fibrinogen is no longer visible. However, in plasma lacking factor XII or HK, fibrinogen remains detectable at times when it is undetectable in normal plasma. The phenomenon of the Vroman effect is explained by the mechanism of surface-dependent activation of factor XII, which both directly and indirectly (through the formation of kallikrein) generates HKa from HK. HKa (but not HK) displaces fibrinogen from the surface.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Coagulation↗
PubMed1975

[Activation of the blood coagulation system during gram-negative infections and endotoxemias].

Blood coagulation may be activated by the extrinsic or intrinsic pathways. The extrinsic clotting system is put into action by tissue thromboplastin, originating from injured tissue cells, but also from damaged leukocytes and erythrocytes. Tissue thromboplastin is a phospholipoprotein with an enzymatic component, capable of converting the clotting factor VII to its activated form, factor VIIa, which in turn activates factor X. The factor Xa-complex (containing also factor Va, phospholipid, and calcium) is the prothrombinconverting principle. The intrinsic clotting system is based on factors which are contained in the circulating blood. Its activation requires the availability of phospholipid and of activated factor XII (factor XIIa), or factor XIa. Factor XII is activated by collagen, i.e., whenever the vascular endothelium is injured, and to a lesser extent also by "activated" blood platelets. Platelets in turn are activated primarily by thrombin, collagen, and, in a self-perpetuating process, since all these materials are released from activated platelets, also by adenosine-5-diphosphate, adrenaline, and serotonin. The activation of platelets leads to a variety of morphological and biochemical alterations, culminating in their aggregation and in the selective release from storage organelles of different substances, among them those mentioned above. Of particular importance is the fact that in the course of platelet alterations, procoagulant phospholipid also becomes available on the platelet surface. The significance of the activation of the intrinsic system is seen in the possibility of the initiation of a self-sustained process which, after a primary event, e.g. vascular or cellular injury, will continue to convert prothrombin into thrombin. The effects of endotoxin on the blood clotting system show striking species differences. In the rabbit, endotoxin, with the involvement of factors of the complement system, will directly act upon blood platelets and thus initiate intravascular, intrinsic coagulation. In man, endotoxin remains without a direct effect on platelets and alternative possibilities of initiating thrombin formation must be considered. One possibility is extrinsic activation via tissue thromboplastin from injured leukocytes. Another pathway, which is supported by several experimental findings, starts out with endotoxin-mediated endothelial damage. Endothelial cells are in fact severely affected by endotoxin and may even be removed from the vascular wall, thus making accessible the subendothelial activator of factor XII. Thrombin in turn affects the vascular endothelium: therefore, one initiated, the process of intravascular activation of coagulation will perpetuate, this the more as platelets in turn will be stimulated into activity. The possible intervention of other vasoactive factors must also be considered...

Animals↗
PubMed1993

The contact system in human malignant and benign ascites.

The plasma contact system was studied in ascites and plasma from patients with gastrointestinal cancer and patients with liver failure. Our study demonstrates the presence of factor XII, factor XI, and prekallikrein and their main inhibitors in ascites and plasma from both patient groups. Both factor XII-like and plasma kallikrein-like activities were detected in the malignant ascites. The kallikrein-like activity in malignant ascites was found in complex with alpha 2-macroglobulin. In plasma samples from the patients functional values of factor XII and prekallikrein were decreased compared to controls. In benign ascites the proenzyme levels were significantly lower than in malignant ascites. Functional inhibition values in ascites and plasma from patients were unexpectedly high. Our findings indicate that the plasma contact system is activated in the ascites from cancer patients. Activation of the contact system generates vasoactive mediators, which may play a role in the accumulation of malignant ascites.

Aged↗
PubMed1979

Factor XII-dependent fibrinolysis: a double function of plasma kallikrein and the occurrence of a previously undescribed factor XII- and kallikrein-dependent plasminogen proactivator.

Fibrinolytic studies in euglobulin fractions of Fletcher trait plasma (deficient in prekallikrein) revealed reduced activities as compared to normal plasma. A quantitative assay for total plasminogen activator plus proactivator in plasma showed that the amount in Fletcher trait patients is about half of normal (normal = +/- 100 blood activator units [BAU]/ml). Plasma kallikrein partially purified in a high and low molecular weight form exerted plasminogen activator activity amounting to 10-15 BAU/ml plasma. So, the absence of kallikrein in the deficient plasma cannot fully account for the reduction in activator activity. Additions of kallikrein preparations or normal plasma fractions resulted in additional activator activity in Fletcher trait plasma which was assessed at 30-40 BAU/ml. This activity was assumed to originate from a previously undescribed plasminogen proactivator whose activation is kallikrein- and factor XII-dependent. Fractionation experiments demonstrated the presence of two major activities and a minor activity caused by kallikrein in normal plasma. It is concluded that plasma kallikrein has two functions in the generation of factor XII-dependent fibrinolytic activity: one as a direct plasminogen activator and another as a factor in the activation of a major factor XII-dependent plasminogen proactivator.

Factor XII↗
PubMed2000

Removal of IgG from normal plasma and plasma from untreated patients with active Crohn's disease--effect on levels of contact factors.

Protein G columns were used to remove IgG from human plasma, and the effect on levels of factor XII, factor XI and prekallikrein was studied in functional tests. IgG was detected in PAGE immunoblot experiments with Fc-specific antibodies. Removal of the bulk of IgG in a procedure based on a low plasma dilution (1+2.5) allowed the passage of an IgG fraction along with the contact factors. This fraction was found to be present in higher amounts in plasma from patients with Crohn's disease (n=5) than in control plasma (n=12). In a previous study, PAGE immunoblot experiments showed that part of the prekallikrein was removed along with IgG when a higher plasma dilution (1+10.8) was used (Scand J Clin Lab Invest 1999; 59: 55-64). This observation was supported by results in the present work based on parallel assays with the peptide substrates S-2302 and Bz-Pro-Phe-Arg-pNA. The prekallikrein fraction removed was present in a functional state differing from the main part of prekallikrein by yielding kallikrein with a significantly increased activity against the substrate S-2366. This prekallikrein fraction was present in higher amounts in patient plasma than in control plasma. Part of the corresponding amidase activity was blocked by lima bean trypsin inhibitor, suggesting its presence in association with factor XI. The results also indicated that prekallikrein activator activity was connected with this fraction. With the high dilution procedure an extensive removal of IgG from the patient plasma was obtained compared to the control plasma.

Adult↗
PubMed1989

Contact phase of blood coagulation is not activated in edema of high altitude.

To examine whether bradykinin generated by the activation of the contact phase of blood coagulation is involved in the pathogenesis of edema occurring after acute exposure to high altitude, 15 mountaineers were examined at 490 m and 1, 3, and 5 days after arrival at 4,559 m. The clotting activity levels of factor XII, factor XI, plasma prekallikrein, and high-molecular-weight kininogen (HMWK) were measured, and plasma kallikrein-induced proteolytic cleavage of HMWK was assessed by ligand blotting by use of radiolabeled factor XI. After an ascent on foot from 1,170 to 4,559 m in 3 days, three subjects developed high-altitude pulmonary edema, and four subjects presented facial edema. There was no evidence for activation of the contact system in any subject as demonstrated by the lack of proteolytic cleavage of HMWK at high altitude. The absence of contact system activation was further supported by stable plasma levels of the individual factors of contact activation. Therefore, we conclude that bradykinin generated by plasma kallikrein-induced cleavage of HMWK is not involved in the pathogenesis of edema due to acute exposure to high altitude.

Altitude Sickness↗
PubMed1993

Factor XII-independent activation of factor XI in plasma: effects of sulfatides on tissue factor-induced coagulation.

Factor XI (FXI) may be activated in a purified system by thrombin and by autoactivation in the presence of negatively charged substances such as dextran sulfate or sulfatides. The current studies were performed to determine if these processes occur during the coagulation of plasma. FXII--deficient plasma was supplemented with 125I-FXI and clot formation was induced with tissue factor and/or sulfatides. Cleavage of FXI was studied by standard polyacrylamide gel electrophoresis and autoradiography. Activated FXI (FXIa) was detected after 20 minutes of incubation with sulfatides alone and this process was markedly accelerated by the addition of tissue factor (TF). The enhancing effect of TF was blocked by hirudin, which indicated thrombin involvement in FXI activation. The contribution of FXIa to FIX activation in this system was studied using a 3H-FIX activation peptide release assay. Sulfatides increased FIX activation about twofold in plasma induced to clot with TF but had no effect if the plasma was immunodepleted of FXI. FIX activation was also increased in plasma induced to clot with FXa if sulfatides were present. The enhanced generation of FIXa was dependent on FXI and was blocked by hirudin. Some activation was seen in the reactions with sulfatides and hirudin and is likely solely caused by FXI autoactivation. The data indicate that during the coagulation of plasma in the presence of sulfatides, FXI is activated by a mechanism that is thrombin dependent and does not require FXII.

Blood Coagulation↗
PubMedDate not supplied

Evaluation of the clotting defect in a factor XII-deficient kindred.

A family with factor XII severe congenital deficiency is described. Factor XII activity and factor XII antigen were both undetectable in the propositus plasma; levels of FXII:C and FXII:Ag were intermediate in heterozygotes. Plasma prekallikrein activity was low in the propositus, whereas normal levels of antigen could be found, suggesting a defect of kallikrein activation due to factor XII deficiency.

Blood Coagulation↗
PubMed1996

Factor XII-induced mitogenesis is mediated via a distinct signal transduction pathway that activates a mitogen-activated protein kinase.

Clotting factor XII (Hageman factor) contains epidermal growth factor (EGF)-homologous domains and is reported to be a potent mitogen for human hepatoma (HepG2) cells. In this study, we tested whether factor XII exhibits growth factor activity on several other EGF-sensitive target cells, including fetal hepatocytes, endothelial cells, alveolar type II cells, and aortic smooth muscle cells. We found that factor XII significantly enhanced [3H]thymidine incorporation in aortic smooth muscle cells (SMCs) and all other cells tested. Tyrphostin, a growth factor receptor/tyrosine kinase antagonist, inhibited both EGF- and factor XII-induced responses. However, differences in the levels of magnitude of DNA synthesis, the observed synergism between EGF and factor XII, and the differential sensitivity to tyrphostin suggest that the EGF receptor and the factor XII receptor may be nonidentical. The factor XII-induced mitogenic response was achieved at concentrations that were 1/10th the physiologic range for the circulating factor and was reduced by popcorn inhibitor, a specific factor XII protease inhibitor. Treatment of aortic SMCs with factor XII, as well as activated factor XII, resulted in a rapid and transient activation of a mitogen-activated/extracellular signal-regulated protein kinase with peak activity/tyrosine phosphorylation observed at 5 to 10 min of exposure. Taken together, these data (i) confirm that clotting factor XII functions as a mitogenic growth factor and (ii) demonstrate that factor XII activates a signal transduction pathway, which includes a mitogen-activated protein kinase.

Animals↗
PubMed1991

Protein adsorption from human plasma is reduced on phospholipid polymers.

Protein adsorption from human plasma was investigated on phospholipid polymers, poly (2-methacryloyloxyethyl phosphorylcholine (MPC)-co-n-butyl methacrylate (BMA) or glass by radioimmunoassay and immunogold labeling techniques. In the present studies the focus was to determine the composition and distribution of proteins at the surface of these materials after contact with human blood plasma. On all materials, protein adsorption was detected and included identification of albumin, IgG, fibrinogen, fibronectin, Hageman factor (factor XII), factor VIII/von Willebrand factor, high-molecular-weight kininogen (HMWK) and the complement protein C5. The amount of protein adsorbed decreased with an increase in the MPC composition and appeared to adsorb to the surfaces in a uniform and evenly distributed manner. Therefore, we suggest that MPC moieties play an important role in suppression of protein adsorption. From these findings, it is concluded that the reduction of protein adsorption at the blood contacting surface of phospholipid polymers may result in the inhibition of thrombus formation.

Adsorption↗
PubMed2003

On the mechanism of inhibition of tissue factor pathway by the synthetic pentasaccharide during coagulation of human plasma.

The tissue factor (TF) pathway is preponderant in the initiation of blood coagulation in normal haemostasis and in thrombotic states. In the present study we investigated the mechanisms by which the synthetic pentasaccharide may influence the regulation of the TF pathway during clotting of human platelet poor plasma (PPP). Clotting of normal PPP or plasmas immuno-depleted of a single clotting factor (factor VII, factor XII, factor XI, factor IX, factor VIII, factor X, factor V, factor II) was initiated by triggering the TF pathway in the presence of fondaparinux (0.5 microg/ml). Activated factor VII (FVIIa) levels were measured in serum obtained at several time intervals after re-calcification of PPP. A clotting assay highly specific for FVIIa was used. The synthetic pentasaccharide inhibited the generation of FVIIa by 66%. The inhibitory effect of fondaparinux on FVIIa was completely abolished when antithrombin activity of plasma was inhibited by a specific antibody. Following the activation of TF pathway in plasmas depleted of factor X or factor IX, the inhibitory effect of fondaparinux on FVIIa generation was completely abolished, whereas it was not significantly modified when the other clotting factor-depleted plasmas were clotted. When fondaparinux was added in the serum, after the maximal generation of FVIIa, it inhibited by 20-30% the activity of the FVIIa-TF complex. These data suggest that fondaparinux enhances the antithrombin-dependent downregulation of the TF pathway by decreasing the generation of FVIIa via the inhibition of the generation and the activity of activated factor IX and activated factor X, and by inhibiting the activity of the FVIIa-TF complex.

Blood Coagulation↗
PubMed1986

High molecular weight kininogen binds to unstimulated platelets.

Studies were performed to determine if the unstimulated platelet membrane has a site for high molecular weight kininogen (HMWK) binding. 125I-HMWK bound to unstimulated platelets. Zn++ was required for 125I-HMWK binding to unstimulated platelets and binding was maximal at 50 microM Zn++. Neither Mg++ nor Ca++ substituted for Zn++ in supporting 125I-HMWK binding to unstimulated platelets, and neither ion potentiated binding in the presence of 50 microM zinc. 125I-HMWK competed with equal affinity with HMWK for binding, and excess HMWK inhibited 125I-HMWK-platelet binding. Only HMWK, not prekallikrein, Factor XII, Factor XI, Factor V, fibrinogen, or fibronectin inhibited 125I-HMWK-platelet binding. 125I-HMWK binding to unstimulated platelets was 89% reversible within 10 min with a 50-fold molar excess of HMWK. Unstimulated platelets contained a single set of saturable, high affinity binding sites for 125I-HMWK with an apparent dissociation constant of 0.99 nM +/- 0.35 and 3,313 molecules/platelet +/- 843. These studies indicate that the unstimulated external platelet membrane has a binding site for HMWK that could serve as a surface to modulate contact phase activation.

Binding, Competitive↗
PubMed2005

Ovarian cancer, the coagulation pathway, and inflammation.

Epithelial ovarian cancer (EOC) represents the most frequent cause of death in the United States from a cancer involving the female genital tract. Contributing to the overall poor outcome in EOC patients, are the metastases to the peritoneum and stroma that are common in this cancer. In one study, cDNA microarray analysis was performed on fresh tissue to profile gene expression in patients with EOC. This study showed a number of genes with significantly altered expression in the pelvic peritoneum and stroma, and in the vicinity of EOC implants. These genes included those encoding coagulation factors and regulatory proteins in the coagulation cascade and genes encoding proteins associated with inflammatory responses. In addition to promoting the formation of blood clots, coagulation factors exhibit many other biologic functions as well as tumorigenic functions, the later including tumor cell proliferation, angiogenesis, invasion, and metastasis. Coagulation pathway proteins involved in tumorigenesis consist of factor II (thrombin), thrombin receptor (protease-activated receptors), factor III (tissue factor), factor VII, factor X and factor I (fibrinogen), and fibrin and factor XIII. In a recent study we conducted, we found that factor XII, factor XI, and several coagulation regulatory proteins, including heparin cofactor-II and epithelial protein C receptor (EPCR), were also upregulated in the peritoneum of EOC. In this review, we summarize evidence in support of a role for these factors in promoting tumor cell progression and the formation of ascites. We also discuss the different roles of coagulation factor pathways in the tumor and peritumoral microenvironments as they relate to angiogenesis, proliferation, invasion, and metastasis. Since inflammatory responses are another characteristic of the peritoneum in EOC, we also discuss the linkage between the coagulation cascade and the cytokines/chemokines involved in inflammation. Interleukin-8, which is considered an important chemokine associated with tumor progression, appears to be a linkage point for coagulation and inflammation in malignancy. Lastly, we review findings regarding the inflammatory process yielded by certain clinical trials of agents that target members of the coagulation cascade in the treatment of cancer. Current data suggest that disrupting certain elements of the coagulation and inflammation processes in the tumor microenvironment could be a new biologic approach to cancer therapeutics.

Journal Article↗