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PubMed1977

Participation of Hageman factor dependent pathways in human disease states.

Abnormalities of Hageman factor dependent pathways have been described in a wide variety of human disease states. Congenital deficiencies of factor XII (Hageman trait) prekallikrein (Fletcher trait) and high molecular weight kininogen (Williams, Fitzgerald and Flaujeac traits) although resulting in profound in vitro changes, do not cause in vivo difficulties. In contrast, deficiency of C1 esterase inhibitor (hereditary angioedema) results in significant morbidity and mortality. Acquired diseases may exhibit decreased synthesis of these three proteins in cirrhosis and dengue fever. In vivo activation of factor XII initiated pathways occur in septic shock, disseminated or localized intravascular coagulation, typhoid fever, polycythemia vera, hyperbetalipoproteinemia, coronary artery disease, nephrotic syndrome, transfusion reactions, hemodialysis and extracorporeal bypass. Activation of both the intrinsic system and tissue mediators contribute to the vasomotor phenomena in carcinoid syndrome and postgastrectomy dumping. Roles for factor XII, prekallikrein and kininogen have been suggested in gouty arthritis, allergic disorders and cystic fibrosis but the evidence is not yet convincing in these disorders.

Angioedema↗
PubMed2000

Preferential consumption of coagulation factors I, V, and VIII in rat endotoxemia.

To ascertain the time course of prolonged coagulation time and the coagulation factors that were consumed preferentially after injection of Escherichia coli endotoxin (ETX, 3 mg/kg, intravenously) in rats, the activated partial thromboplastin time (aPTT) and prothrombin time (PT) were measured. Using aPTT and PT, the residual levels of the major coagulation factors were quantified by partial replacement of ETX-injected rat plasma with individual factor-deficient human plasma. The residual levels of prekallikrein and high molecular weight (HMW) kininogen were also measured. After ETX injection, aPTT and PT showed gradual increasing prolongation, which was marked at 3-5 h after the injection. The residual level of fibrinogen was markedly reduced between 1 and 3 h after ETX injection and dropped to the determination limit 7 h after the injection. Ratios of the consumed coagulation factors, prekallikrein, and HMW kininogen in rat plasma collected 7 h after intravenous injection of ETX were obtained as follows: prekallikrein (18.0 +/- 4.8%), HMW kininogen (36.2 +/- 1.9 %), factor XII (54.0 +/- 0.7%), factor VIII (86.1 +/- 1.8%), factor VII (35.6 +/- 7.7%), factor V (90.6 +/- 0.8%), and factor I (fibrinogen) (>89.6 +/- 0.0%). Thus, coagulation factor I (fibrinogen) and factors V and VIII (cofactors) were consumed preferentially. The extrinsic coagulation pathway was dominantly activated, whereas the intrinsic coagulation pathway, including plasma kallikrein-kinin system, played less important role in the ETX-induced consumption coagulopathy in rat.

Animals↗
PubMed1988

Quantification of plasma factor XIIa-Cl(-)-inhibitor and kallikrein-Cl(-)-inhibitor complexes in sepsis.

Considerable evidence indicates that activation of the contact system of intrinsic coagulation plays a role in the pathogenesis of septic shock. To monitor contact activation in patients with sepsis, we developed highly sensitive radioimmunoassays (RIAs) for factor XIIa-Cl(-)-inhibitor (Cl(-)-Inh) and kallikrein-Cl(-)-Inh complexes using a monoclonal antibody (MoAb Kok 12) that binds to a neodeterminant exposed on both complexed and cleaved Cl(-)-Inh. Plasma samples were serially collected from 48 patients admitted to the intensive care unit because of severe sepsis. Forty percent of patients on at least one occasion had increased levels of plasma factor XIIa-Cl(-)-Inh (greater than 5 x 10(-4) U/mL) and kallikrein-Cl(-)-Inh (greater than 25 x 10(-4) U/mL), that correlated at a molar ratio of approximately 1:3. Levels of factor XII antigen in plasma and both the highest as well as the levels on admission of plasma factor XIIa-Cl(-)-Inh in 23 patients with septic shock were lower than in 25 normotensive patients (P = .015: factor XII on admission; P = .04: highest factor XIIa-Cl(-)-Inh; P = .01: factor XIIa-Cl(-)-Inh on admission). No significant differences in plasma kallikrein-Cl(-)-Inh or prekallikrein antigen were found between these patients' groups. Elevated Cl(-)-Inh complex levels were measured less frequently in serial samples from patients with septic shock than in those from patients without shock (P less than .0001). Based on these results, we conclude that plasma Cl(-)-Inh complex levels during sepsis may not properly reflect the extent of contact activation.

Adolescent↗
PubMed1977

Hageman factor and disseminated intravascular coagulation (DIC) in newborns and rabbits.

There was no significant difference in the levels of factor XII between sick newborns and normal age-matched controls, although the levels of both groups were lower than normal older children. Detailed coagulation studies on 44 sick infants revealed 11 to have disseminated intravascular coagulation (DIC). In those with DIC, the mean Hageman factor was 20% and in those without DIC, 25% (P greater than 0.05). Rabbits given a constant infusion of lysozyme (which inhibits factor XII) showed laboratory evidence of endotoxin-induced DIC. The data suggest that neither reduced factor XII levels nor Hageman factor inhibition provided protection from DIC. The data further suggest that other coagulation pathways might be involved in order to elicit the DIC.

Animals↗
PubMed2002

The contact system.

OBJECTIVES: To review the literature for conditions, diseases, and disorders that affect activity of the contact factors, and further to review the literature for evidence that less than normal activity of any of the contact factors may be associated with thrombophilia. DATA SOURCES: MEDLINE search for English-language articles published from 1988 to 2001 and pertinent references contained therein, as well as search of references in recent relevant articles and reviews. STUDY SELECTION: Relevant clinical and laboratory information was extracted from selected articles. Meta-analysis was not feasible because of heterogeneity of reports. DATA EXTRACTION AND SYNTHESIS: Evidence for association of altered levels of the contact factors and thrombophilia was sought. A wide variety of disorders is associated with decreased activity of the contact factors; chief among these disorders are liver disease, hepatic immaturity of newborns, the antiphospholipid syndrome, and, for factor XII, being of Asian descent. These disorders are more common than homozygous deficiency. The few series and case reports of thrombophilic events in patients homozygous for deficiency of contact factors are not persuasive enough to support causality. The apparent association between levels consistent with heterozygosity (40%-60% of normal) of any of the contact factors (but especially factor XII) in persons with antiphospholipid antibodies appears to be due to falsely decreased in vitro activity levels of these factors, which are normal on antigenic testing. The apparent association with thrombosis is better explained by the antiphospholipid syndrome than by the modest reduction of the levels of contact factors. CONCLUSIONS: Presently, it is not recommended to measure activity of contact factors during routine evaluation of patients who have suffered venous or arterial thromboembolism or acute coronary syndromes.

Blood Coagulation↗
PubMed1974

Activation of Hageman factor and initiation of hepatic vein thrombosis in the hyperlipemic rat.

Hepatic vein thrombosis initiated by an intravenous injection of endotoxin (Salmonella typhosa, 0.3 mg/kg) resulted in an incidence of 78% in rats fed a butter-rich diet (group 1). On the other hand, no lesion could be produced in control animals fed corn oil (group 2) or standard chow (group 3). In regard to the respective thrombotic tendencies, the rats fed butter showed higher circulating levels of factor XII (175% vs 140% in group 2 and 100% in group 3) and a far more severe decrease in this factor (41% vs 15% in group 2 and 7% in group 3) and in platelets (48% vs 25% in group 2 and 19% in group 3) 2 hours after the injection of endotoxin. The triggering effect of endotoxin could be reproduced by ellagic acid, a known activator of factor XII. Given by slow infusion (1 mg/kg/min) this chemical induced hepatic vein thrombosis in 52% of the rats fed the butter-rich diet. Furthermore, inhibition of factor XII activation by lysozyme (20 mg/kg/min) completely prevented hepatic vein thrombosis initiated by endotoxin in butter-fed animals. It is concluded that, in addition to the potent hypercoagulability induced by the fat-rich diets, activation of Hageman factor consecutive to endotoxin injection is essential for production of the phenomenon of hepatic vein thrombosis.

Animals↗
PubMed1998

Streptokinase-induced activation of the kallikrein-kinin system and of the contact phase in patients with acute myocardial infarction.

Thrombolytic therapy in acute myocardial infarction (AMI) is hampered by a considerable reocclusion rate. Thrombin activity is enhanced, and contact-system activation via plasminemia might be possible. Prospectively we examined the contact phase and the kallikrein-kinin system and additional molecular markers of hemostasis and fibrinolysis in AMI. In 22 patients with AMI, blood sampling was performed at admission and < or =10 days afterward. Eleven patients received 1.5 Mio U streptokinase (group A) and were compared with 11 AMI patients without thrombolytic therapy (group B). All patients had systemic heparinization (5,000 IU bolus, i.v.; 1,000 IU/h, i.v.). In group A (vs. group B), the kallikrein-factor XII system was significantly activated (3 h after start of therapy): kallikrein activity 140 +/- 41 (vs. 43 +/- 8) U/L (p < 0.05); kallikrein inhibition 87 +/- 9 (vs. 113 +/- 7%; p < 0.05), and factor XII 70 +/- 14 (vs. 94 +/- 6%). C1 inhibitor and factor XII inhibition were decreased. High-molecular-weight kininogen consumption indicating bradykinin generation was enhanced (p < 0.01). In group A, thrombin activity (TAT) was increased, and a hypercoagulative state with increased fibrin degradation products (d-dimer) was found. Plasmin activation in group A was reflected by decreased plasminogen and antiplasmin levels (p < 0.01). The findings indicate that streptokinase induces activation of the contact phase-kinin system in vivo associated with a consecutive increase of thrombin and bradykinin generation. Activation of this pathway might substantially contribute to reocclusion after initially successful thrombolytic therapy and to hypotensive reactions observed after streptokinase.

Acute Disease↗
PubMed1999

Cytokeratin 1 and gC1qR mediate high molecular weight kininogen binding to endothelial cells.

High molecular weight kininogen (HK) attaches to endothelial cells by separate sites on the heavy and light chains and requires 15-50 microM zinc. Previously identified binding proteins include gC1qR, cytokeratin 1, and the urokinase plasminogen activator receptor; however, their relative contributions to binding are not yet clarified. We have prepared affinity columns to which were coupled either cleaved HK or peptide LDCNAEVYVVPWEKKIYPTVNCQPLGM derived from heavy-chain domain 3. Endothelial cell membranes were solubilized and chromatographed in the presence or absence of zinc ion, the bound proteins were eluted, and active fractions were identified by dot blot using biotinylated HK, SDS/PAGE, and Western blot analysis. The peptide containing column eluate revealed but one band at 68 kDa if zinc ion was present which was identified as cytokeratin 1 by amino acid sequencing of an internal peptide. The HK affinity column revealed bands at 68 kDa (cytokeratin 1), 33 kDa (gC1qR), and 66 kDa (unidentified). HK or domain 3-derived peptide bound to the 68 kDa band; prekallikrein and Factor XII did not. HK or Factor XII bound to the 33-kDa band if zinc was present while no binding to the 66 kDa band was observed. Antibody to cytokeratin 1 inhibited HK binding to endothelial cells by 30%, antibody to gC1qR inhibited HK binding to endothelial cells by 72%, and a mixture of both inhibited binding by 86%. Our data suggest HK binding by interaction of the heavy-chain domain 3 with cytokeratin 1 and the light chain with gC1qR.

Amino Acid Sequence↗
PubMed1995

Alterations of coagulation and fibrinolytic and kallikrein-kinin systems in the acute and postacute phases in patients with unstable angina pectoris.

BACKGROUND: Unstable angina pectoris is frequently associated with intracoronary thrombus formation. In a prospective study, we investigated in 35 patients with unstable angina pectoris markers of coagulation and the kallikrein-kinin and fibrinolytic systems in the acute and postacute phases. METHODS AND RESULTS: We determined serially in the patients up to 10 days after admission factor XII and the beta-factor XIIa inhibition, kallikrein-like activity, prekallikrein, C1-esterase inhibitor, kallikrein inhibition, high molecular weight kininogen as indicators of the contact phase and bradykinin generation, thrombin-antithrombin III (TAT) complex as marker of the activated coagulation cascade, fibrinogen, plasminogen, plasminogen activator inhibitor-1 (PAI-1), tissue-type plasminogen activator (TPA), and D-dimers as indicators of the fibrinolytic system. Data were compared with those from control subjects (n = 25) and from patients with stable angina pectoris (n = 25). In patients with unstable angina pectoris, initially the contact phase and the kallikrein-kinin system were markedly elevated (factor XII, 96 +/- 5% versus 117 +/- 5%; kallikrein-like activity, 35.7 +/- 2.9 versus 27.4 +/- 1.3 U/L; high molecular weight kininogen, 52.7 +/- 5.2% versus 87.7 +/- 3.9%; P < .01 versus control subjects). Contact-phase activation persisted for the following 10 days, whereas the initially enhanced bradykinin generation normalized after 2 days. Furthermore, we had evidence of a hypercoagulative state (TAT, 10.9 +/- 3.1 versus 4.5 +/- 0.7 micrograms/L, P < .05; D-dimer, 474 +/- 81 versus 272 +/- 71 ng/mL) persisting longer than the clinically symptomatic period in association with disturbed fibrinolysis (TPA, 15.9 +/- 1.9 versus 5.1 +/- 0.4 ng/mL; P < .01; PAI-1, 9.9 +/- 2.6 versus 4.6 +/- 1.6 AU/mL; P = NS) in the presence of elevated fibrinogen levels. CONCLUSIONS: Our data indicate that in patients with unstable angina pectoris, intracoronary thrombus formation is associated with a hypercoagulative state, including activation of the contact phase and of the kallikrein system and increased bradykinin generation. The persistence of this hypercoagulative state, together with a disturbed fibrinolysis, might indicate an increased risk for further coronary events.

Acute Disease↗
PubMed2002

Suppressed intrinsic fibrinolytic activity by monoclonal anti-beta-2 glycoprotein I autoantibodies: possible mechanism for thrombosis in patients with antiphospholipid syndrome.

beta2-glycoprotein I (beta2GPI) bears the epitope(s) for autoimmune anticardiolipin antibodies (aCL) frequently present in patients with antiphospholipid syndrome (APS). beta2GPI is involved in coagulation and fibrinolytic systems, including inhibition of contact activation. Coagulation factor XII is an initiator of intrinsic coagulation and also of intrinsic fibrinolysis. We investigated the effect of aCL (= anti-beta2GPI antibodies), regarding intrinsic fibrinolysis using autoimmune monoclonal anti-beta2GPI antibodies derived from a patient with APS or from an NZW/BXSB-F1 mouse. We developed a chromogenic assay system to determine intrinsic fibrinolytic activity. The reaction was activated by kaolin in the euglobulin fraction. Exogenous beta2GPI slightly suppressed intrinsic fibrinolytic activity of the euglobulin fraction from normal plasma. Human monoclonal anti-beta2GPI antibody (EY2C9) and mouse monoclonal anti-beta2GPI antibody (WBCAL-1) in the presence of beta2GPI decreased the activity. In this system, the suppression remained significant in the presence of an excess of exogenous activated factor XII. Euglobulin fractions from APS patients' plasma paralleled low activities of intrinsic fibrinolysis compared with those from healthy subjects. Our results suggest that beta2GPI and anti-beta2GPI antibodies suppress intrinsic fibrinolytic activities. This suppression was not only due to inhibition of factor XII activation but was also related to function of activated factor XII (XIIa). These phenomena partly explain the mechanisms of thrombosis in APS.

Antibodies, Monoclonal↗
PubMed2005

Subdural hematoma in a patient with Hageman trait--case report.

A 61-year-old man with severe factor XII deficiency presented with a subdural hematoma appearing as mixed but mainly high density by computed tomography in the left frontotemporoparietal region. No cranial injury was reported in the medical history of the patient. Clotting system study showed less than 1% functional activity of factor XII, whereas the levels of the other clotting factors were within the normal ranges. Partially clotted and hemolyzed subdural hematoma was removed through a craniotomy. The postoperative course was uneventful. The patient later died of severe circulatory-respiratory failure. We believe that the subdural hematoma may have developed as a result of a minor head trauma sustained in the past. We suggest that impairment of fibrinolytic activation related to severe factor XII deficiency might have contributed to the delay of dissolution of the subdural hematoma which, under ordinary circumstances, would have formed chronic subdural hematoma.

Factor XII Deficiency↗
PubMed1979

Evidence against collagen activation of platelet-associated factor XI as a mechanism for initiating intrinsic clotting.

Collagen activation of platelet-associated Factor XI has been proposed as a mechanism for initiating intrinsic clotting independent of Factor XII. Since this could explain the lack of bleeding in patients with hereditary Factor XII deficiency, prekallikrein deficiency and high molecular weight kininogen deficiency, we subjected the hypothesis to rigorous testing. Incubation of isolated platelets with collagen and calcium ions failed to generate activity shortening the clotting time of an activated Factor XI (XIa) assay that had been modified to eliminate effects due to platelet-associated activated Factor V. Nor could generation of traces of Factor XIa in such mixtures be detected by incubation with purified Factor IX and testing for the generation of activated Factor IX (IXa) in clotting and amidolytic assays. Moreover, when blood or platelet-rich plasma containing added 125I-Factor IX was incubated with calcium ions and collagen and then subjected to reduced sodium dodecyl sulfate polyacrylamide gel electrophoresis, the radioactivity profiles revealed only native 125I-Factor IX without evidence of the polypeptide chains of Factor IXa. The negative results of this study mitigate against the hypothesis that collagen activation of platelet-associated Factor XI represents a physiologically significant mechanism for initiating clotting independent of Factor XII.

Animals↗
PubMed1983

Amino acid sequence of human beta-factor XIIa.

Human factor XII was activated by limited proteolysis with trypsin, and the resulting beta-factor XIIa (Mr = 30,000) was isolated by DEAE-Sephacel column chromatography. The complete amino acid sequence of beta-factor XIIa was then determined on peptides produced by enzymatic digestion with either trypsin, chymotrypsin, or Staphylococcus aureus V8 protease and by chemical cleavage at methionyl and tryptophyl bonds. beta-Factor XIIa is a glycoprotein composed of a heavy chain (243 amino acid residues) and a light chain (9 amino acid residues), and these two chains are held together by a disulfide bond. The carbohydrate is attached to asparagine residue 61 in the heavy chain. The amino acid sequence of the heavy chain shows a high degree of homology to the corresponding regions of other plasma serine proteases, such as plasmin, thrombin, factor IXa and factor Xa, as well as the pancreatic digestive enzymes. These results demonstrate that factor XII is the precursor of a typical serine protease that participates in the coagulation cascade.

Amino Acid Sequence↗
PubMed1987

Effect of negatively charged activating compounds on inactivation of factor XIIa by Cl inhibitor.

Human factor XII, upon exposure to negatively charged surfaces such as kaolin, sulfatides, and heparin, is converted to enzymatic forms, factor XIIa and factor XIIf. Cl inhibitor has been quantitatively demonstrated to be the primary plasma inhibitor of both factor XIIa and factor XIIf. Studies were performed to determine whether the presence of artificial, negatively charged surfaces influenced the ability of Cl inhibitor to inhibit factors XIIa and XIIf. Kaolin and sulfatides slowed the rate of inhibition of factor XIIa by Cl inhibitor 4.8- and 2-fold, respectively, whereas they had no effect on the inhibition of factor XIIf by Cl inhibitor. Heparin in a concentration of 65 U/ml decreased the inhibition rate of factor XIIa by Cl inhibitor, but, at the same concentration, had less of an effect on the ability of Cl inhibitor to inhibit factor XIIf. These studies indicate that negatively charged surfaces protect factor XIIa but not factor XIIf from inhibition from Cl inhibitor. Since the difference between factors XIIa and XIIf consists of the presence of a surface binding region in factor XIIa, the basis of this protection must reside in the surface binding residues of factor XII. These in vitro events suggest that surface-bound factor XIIa may hydrolyze its physiologic substrates, factor XI and prekallikrein, in an environment partially protected from inhibition by Cl inhibitor.

Complement C1 Inactivator Proteins↗
PubMed1982

[Use of chromogenic substrates in the clarification of disorders in the early stages of blood coagulation].

The kallikrein specific chromogenic peptide substrates S-2302 (KABI) and Chromozym PK (Boehringer) were used in the first analysis of a familial defect in the early stage of clotting. Slight to extensive prolongation of the activated partial thromboplastin time was seen in the affected persons. Using dextransulfate for activation of plasma marked deficiency in kallikrein activity was found in 3 persons. Using factor XIIa (activated Hageman factor) for activation normal prekallikrein levels were found in 2 of them whereas factor XII levels, however, were below normal. The third had a prekallikrein deficiency presumably caused by oral contraceptives. In a fourth member of the family factor XII deficiency was found with normal kallikrein activity. The application of chromogenic peptide substrates for analysing the early stage of clotting has to take into account the special mechanisms of activation.

Adolescent↗
PubMed1983

Initiation of contact activation by sulfatides.

Low amount of sulfatides initiated intrinsic coagulation and the appearance of kallikrein activity in normal human plasma. The initiation of procoagulant and kallikrein amidolytic activity was dependent on the presence of Factorr XII, high molecular weight kininogen and prekallikrein. Because the activated partial thromboplastin clotting times in prekallikrein deficient plasma approach normal values upon prolonged incubation with kaolin, this phenomenon was studied and found to be even more pronounced in the presence of sulfatides. Shortening of the clotting time was essentially completed in 5 min in the presence of sulfatides whereas a pre-incubation of 15 to 20 min was required in the presence of kaolin. The limited proteolysis of 125I-Factor XII in plasma during incubation was more rapid and more extensive in the presence of sulfatides than in the presence of kaolin. Factor XII cleavage in prekallikrein deficient plasma was completed in less than 5 min in the presence of sulfatides and in less than 15 min in the presence of kaolin. Thus, the appearance of Factor XII-dependent coagulant activity correlates with the limited proteolysis of Facto XII when normal or prekallikrein deficient plasma is activated by sulfatides or by kaolin. These observations are consistent with the hypothesis that Factor XII is cleaved in plasma to generate maximal Factor XIIa activity.

Animals↗
PubMedDate not supplied

Activation of the plasma kinin forming cascade along cell surfaces.

Proteins of the plasma kinin-forming cascade bind to endothelial cells and activation of the cascade can be initiated along the surface. The light chain of high molecular weight kininogen (HK) (domain 5) and factor XII bind to gC1qR, the heavy chain of HK (domain 3) binds to cytokeratin 1 and the interactions are zinc dependent. Prekallikrein binds to domain 6 of HK. Antisera to gC1qR and cytokeratin 1 inhibit binding and activation. Incubation of normal plasma with endothelial cells leads to gradual conversion of prekallikrein to kallikrein, while plasma deficient in factor XII or HK are inactive within a 2-hour time frame. Thus factor XII is critical for activation to proceed. Augmentation of these reactions may occur when C1 inhibitor is functionally deficient or with ACE inhibitors which also inhibit kininases.

Carrier Proteins↗