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PubMed1986

Purification of Hageman factor (factor XII) on columns of popcorn-agarose.

Purification of Hageman factor (HF, factor XII) from human plasma is a tedious procedure and the product is not always in the precursor form. Hojima has described a protein derived from corn kernels that inhibits the enzymatic properties of HF. This inhibitor binds to the precursor form of HF. Rapid purification of HF was achieved by using as the major purification step adsorption of this clotting factor to popcorn inhibitor bound to agarose. The product had a specific activity of 50.0 to 67.1 coagulant units of HF per milligram protein, and the yield was 33% to 40% of the HF content of the starting plasma. The purified protein displayed a single band upon unreduced or reduced sodium dodecyl sulfate polyacrylamide gel electrophoresis and less than 0.1% was in an activated form, as measured in coagulant assays. The technique described is more rapid and reliable than methods described earlier.

Adsorption↗
PubMed1998

Potent 'new pressor protein' related to coagulation factor XII is potentiated by inhibition of angiotensin converting enzyme.

BACKGROUND: 'New pressor protein' was observed after tryptic activation of human and rat plasma in vitro, which is done conventionally for prorenin measurements. RESULTS: It is potently pressor, heat labile, possesses enzyme activity, and has a relative molecular mass > 30 kDa with isoelectric point(s) 4.7-4.9. New pressor protein equivalent to only 0.01 ml human, or rat, plasma injected intravenously quickly raises systolic blood pressure in 300 g anesthetized, ganglion-blocked, bioassay rats by about 15 mmHg. For unknown reasons, this is potentiated to about 45 mmHg after treatment with angiotensin I converting enzyme inhibitors (such as captopril and enalapril). New pressor protein activity in rats remains normal 24 h after bilateral nephrectomy, suggesting that it has an extrarenal origin and, furthermore, excluding the possibility of an association with renin-angiotensin system. Systolic blood pressure elevation is greater than the diastolic one, implicating cardiotonic effects. Human plasma new pressor protein was purified using standard biochemical techniques and its N-terminal sequence (19 residues) found to be homologous with the beta factor XIIa fragment of coagulation factor XII. This was supported by demonstrating inhibition of new pressor protein activity in vitro using the factor XII-specific corn trypsin inhibitor. Also, human new pressor protein activity in humans congenitally deficient in coagulation factor XII is very low. The high potency and multiphasic, cardiotonic effects of injected new pressor protein suggest that it interacts synergistically with other systems in the body. This was confirmed by showing that, within 10 min of total bilateral adrenalectomy, responses to new pressor protein decreased markedly. CONCLUSIONS: New pressor protein's action requires adrenal (medullary?) involvement, but its mechanism of action and that of its potentiation by angiotensin converting enzyme inhibitors remain unknown. The physiologic and clinical relevance of these observations depends on whether activation of new pressor protein can occur in vivo.

Adrenal Medulla↗
PubMed2005

Demonstration of a threshold response in a proteolytic feedback system: control of the autoactivation of factor XII.

Mathematical analysis of positive feedback loops in proteolytic systems has previously suggested that when the active enzymes are subject to inhibitory control these systems will exhibit threshold behavior. This is demonstrated in the present study, for the autolytic activation of factor XII in the presence of a contact activator and an irreversible inhibitor of factor XIIa. The threshold between the two system states - complete factor XII activation, or complete stability - is dependent on the kinetic balance between the catalytic rate of autoactivation and rate of enzyme (factor XIIa) inhibition. Activation of the system can be brought about by either increasing the catalytic rate (in this study, by using more potent contact-activation conditions), or by lowering the enzyme inhibition rate. Previous mathematical work predicted complete stability in a positive-feedback system that is below threshold, and this has been experimentally confirmed.

Antithrombin III↗
PubMed2006

Hereditary angioedema with normal C1 inhibitor activity including hereditary angioedema with coagulation factor XII gene mutations.

Until recently it was assumed that hereditary angioedema is a disease that results exclusively from a deficiency of the C1 inhibitor. In 2000, families with hereditary angioedema, normal C1 inhibitor activity, and protein in plasma were described; all patients were women. In many of the affected women, oral contraceptives, hormone replacement therapy containing estrogens, and pregnancies triggered the clinical symptoms. Recently, in some families mutations in the coagulation factor XII (Hageman factor) gene were detected in the affected women.

Angioedema↗
PubMed1977

[Effect of immobilized noradrenaline on human plasma arginine esterase activated by factor XII].

An attempt to study direct hormonal regulation of the blood coagulating system by catecholamines, using the affinity chromatography method, was made. It was found that human blood plasma is adsorbed and the enzyme hydrolyzing N-benzoyl-L-arginine, is activated on the column. It was found that human blood plasma after the contact with norepinephrine loses its ability to increase the BAEE-esterase activity, when tanic acid, which activates factor XII (Hageman factor), was added.

Arginine↗
PubMed1998

Factor XII determinations in the presence and absence of phospholipid antibodies.

Factor XII (FXII) levels were determined in plasma samples from 29 normal donors, 10 patients with inherited FXII deficiency (all lupus anticoagulant [LA] negative) and 67 LA positive patients, using clotting (FXIIct), chromogenic substrate (FXIIcs) and immunochemical (FXIIag) assays. Excellent correlations were obtained in the three FXII assays with the LA negative samples and between the FXIIcs and FXIIag assays in the LA positive samples. Correlations between both the FXIIcs and FXIIag with FXIIct in the LA positive patients were poor. Of 67 LA positive samples studied, 25 (37.3%) showed lower values in the FXIIct assay; 13 (19.4%) of these patients were pseudo FXII deficient with values of FXII below the lower limit of normal. These results indicate that a diagnosis of FXII deficiency can be made inappropriately in the presence of phospholipid antibodies and that such a diagnosis should not be made by FXIIct assay alone.

Antibodies, Antiphospholipid↗
PubMed2003

Molecular characterization of coagulation factor XII deficiency in a Japanese family.

We report the identification in a Japanese family of a novel homozygous W486C mutation in the protease domain of coagulation factor XII (FXII), which was associated with the reduction of plasma FXII activity and antigen level to less than 5% of normal. Sequences of each exon for FXII gene was analysed in family members by polymerase chain reaction (PCR) amplification followed by a direct sequencing method. Sequence analysis showed a homozygous substitution of G to C at nucleotide position 10587 (cDNA position 1458) in proband's FXII gene, resulting in a Trp to Cys substitution in the catalytic domain of FXII. PCR-fragment length polymorphism analysis of 55 healthy volunteers showed no such mutation. Transient expression of FXII in HK-293T cells and analysis of FXII antigen in culture media and cell lysates showed reduced secretion of mutant protein by more than 84% relative to that of wild type protein although the intracellular contents were similar. Our results suggest that the reduced secretion of FXII protein was due to incorrect folding caused by the introduction of Cys486. We designated this mutation as FXII Mie-1.

Amino Acid Substitution↗
PubMed2002

Antibodies to factor XII are distinct from antibodies to prothrombin in patients with the anti-phospholipid syndrome.

Patients with the anti-phospholipid syndrome (APS) have antiphospholipid antibodies (aPA) which are often targeted towards phospholipid binding proteins such as beta2-glycoprotein I and prothrombin. Antibodies to factor XII (FXIIabs) have also been identified in some patients with APS. Factor XII (FXII) is a member of the kringle family of proteins which include plasminogen and prothrombin. Antibodies to prothrombin have been associated with myocardial infarction and have been shown to cross react with plasminogen. Sixteen patients with APS and FXIIabs were investigated for the presence of antibodies to prothrombin, by enzyme linked immunosorbent assay in a calcium (Ca++) independent assay. All sixteen showed different antibody binding patterns than those observed for antibodies to FXII. Eight patients were further investigated using surface plasmon resonance (SPR) for antibody binding to covalently bound FXII and to covalently bound prothrombin in both Ca++ dependent and independent systems. Of three patients demonstrating antibody binding to FXII by SPR, none demonstrated antibody binding to prothrombin in a Ca++ independent system with one demonstrating antibody binding to prothrombin that was Ca++ dependent. Of five patients who did not bind FXII by SPR, one demonstrated antibody binding to prothrombin in a Ca++ independent system while two demonstrated antibody binding to prothrombin in a Ca++ dependent system. Antibodies to FXII in patients with APS appear to be distinct from antibodies to prothrombin.

Antibody Affinity↗
PubMed1996

Measurement of activated factor XII in health and disease.

We investigated a new ELISA for measuring activated factor XII (FXIIa) in plasma. The intra-assay coefficient of variation was 3.5% and 5.1% for plasma containing 2.5 and 8.2 ng/ml FXIIa. The inter-assay coefficient of variation was 6.2% and 6.6%. FXIIa correlated with age in women older than 55 years (r = 0.55, P = 0.0003). Mean levels in the whole population of 160 healthy individuals included in this study were not different between men and women, but women younger than 55 years had lower levels than older women and men of the corresponding age. In a group of 25 healthy centenarians FXIIa was significantly higher (3.2 ng/ ml, 95% CI 2.3-3.6) than in controls (2.1 ng/ml, 95% CI 1.8-2.4). Increased levels were also found in pregnancy, with higher levels in the third trimester (4.7 ng/ml, 95% CI 3.9-5.5) than in the first trimester (2.9 ng/ml, 95% CI 2.2-3.9). FXIIa was unmeasurable in patients with FXII deficiency, but normal in patients with FXI deficiency and C1-inhibitor deficiency. FXIIa was significantly higher than in normal controls in patients with severe sepsis (3.9 ng/ml, 95% CI 2.8-5.4) and septic shock (5.4 ng/ml, 95% CI 3.7-7.7). After treatment with thrombolytic agents, a marked increase of FXIIa was found in patients with myocardial infarction. In conclusion, the immunoassay of FXIIa permits to study more directly the contact phase of blood coagulation in situations in which the involvement of this system may play a pathophysiological role.

Adult↗
PubMed1979

Molecular heterogeneity of Hageman trait (factor XII deficiency): evidence that two of 49 subjects are cross-reacting material positive (CRM+).

We have studied plasmas of 49 individuals with homozygous Hageman trait from 42 kindreds, all of which contained less than 1% of the Hageman factor (factor XII) clotting activity of pooled normal plasmas. Forty-seven plasmas contained less than 1% of Hageman factor antigen. In two other, unrelated individuals with Hageman trait, nonfunctional material immunologically indistinguishable from normal Hageman factor was detected in plasma by radioimmunoassay at concentrations of 39% and 80%, respectively. These plasmas did not contain circulating anticoagulants against Hageman factor and, as in ordinary Hageman trait, displayed impaired surface-mediated plasma reactions such as fibrinolysis and kinin generation. Upon immunodiffusion against anti-Hageman factor serum, these plasmas formed a single precipitin line of complete identity with normal plasma or purified Hageman factor. Upon immunoelectrophoresis, the precipitin line had the same mobility as normal Hageman factor. Nonfunctional Hageman factor and normal Hageman factor behaved identically on a Sephadex G-150 column (apparent MW = 100,000) and on sucrose density-gradient centrifugation (4.5S). Nonfunctional Hageman factor was adsorbed to kaolin as readily as normal Hageman factor, suggesting that the binding site to negatively charged surfaces is different from functional sites. Antiserum raised against Hageman factor-like material in a CRM+ Hageman trait plasma specifically inactivated Hageman factor activity in normal plasma. The plasmas of three heterozygotes in these families contained approximately twice as much Hageman factor antigen as Hageman factor activity, whereas those of 16 heterozygotes in ordinary (CRM-) Hageman trait families contained approximately equal amounts of activity and antigen. The present study indicates that rarely homozygous Hageman trait may be CRM+ and that this defect is genetically determined.

Cross Reactions↗
PubMed1977

Feline factor XII (Hageman) deficiency.

A coagulation profile from a clinically normal female cat revealed an intrinsic coagulation defect characterized by prolonged activated partial thromboplastin time, with normal bleeding time, platelet count, and prothrombin time. Subsequent correction studies, utilizing activated partial thromboplastin time, confirmed factor XII deficiency. Hematologic and clinical studies on the cat failed to reveal an underlying disease process that might result in acquired factor XII deficiency.

Animals↗
PubMed2002

A mosquito salivary protein inhibits activation of the plasma contact system by binding to factor XII and high molecular weight kininogen.

The salivary glands of female mosquitoes contain a variety of bioactive substances that assist their blood-feeding behavior. Here, we report a salivary protein of the malarial vector mosquito, Anopheles stephensi, that inhibits activation of the plasma contact system. This factor, named hamadarin, is a 16-kDa protein and a major component of the saliva of this mosquito. Assays using human plasma showed that hamadarin dose-dependently inhibits activation of the plasma contact system and subsequent release of bradykinin, a primary mediator of inflammatory reactions. Reconstitution experiments showed that hamadarin inhibits activation of the plasma contact system by inhibition of the reciprocal activation of factor XII and kallikrein. Direct binding assays demonstrated that this inhibitory effect is due to hamadarin binding to both factor XII and high molecular weight kininogen and interference in their association with the activating surface. The assays also showed that hamadarin binding to these proteins depends on Zn(2+) ions, suggesting that hamadarin binds to these contact factors by recognizing their conformational change induced by Zn(2+) binding. We propose that hamadarin may attenuate the host's acute inflammatory responses to the mosquito's bites by inhibition of bradykinin release and thus enable mosquitoes to take a blood meal efficiently and safely.

Animals↗
PubMed1983

Activation of factor XII in human plasma: protection by benzamidine of the cofactor function of high molecular weight kininogen.

By incubation of human citrated plasma with acetone 25% v/v kallikrein inhibitors were destroyed and prekallikrein activated to kallikrein. When the incubation was carried out in the presence of benzamidine 7 mM, the cofactor capacity of high molecular weight kininogen (HMrK) was protected against destruction by a serine protease which was not plasma kallikrein. By analogy with studies in rat plasma this protease might be a plasminogen activator (Berstad & Briseid 1982; Johansen & Briseid 1983). Factor XII in the plasma preparation was activated to unfragmented factor XIIa by adsorption to kaolin, and assayed as prekallikrein activator (PKA). The extent of activation of factor XII was only insignificantly influenced by the 1 + 1 (v/v) dilution of the plasma preparation with a suspension of kaolin. When, however, the preparation was diluted greater than 1 + 5 (v/v) before incubation with the suspension, a stoichiometric HMrK concentration-effect curve could be established, allowing the assay of cofactor-active HMrK. Assays of HMrK in plasma preparations from healthy men and women demonstrated an average lower level of cofactor-active HMrK in the preparations from women. It is suggested that benzamidine is not capable of providing a complete protection of HMrK during the procedure in all plasma samples.

Adult↗
PubMed1992

Induction of expression of monocyte interleukin 1 by Hageman factor (factor XII).

The results reported here indicate that activated species of Hageman factor (HF, factor XII), a protein that mediates blood clotting, fibrinolysis, and activation of the complement cascade, induce elaboration of interleukin 1 (IL-1) by human monocytes. Augmentation of IL-1 production in mononuclear cell cultures was observed when HF was present along with lipopolysaccharide (LPS) but was not observed with HF alone. Furthermore, antiserum to HF abrogated the enhancement of IL-1 in cultures containing HF and LPS. Total IL-1 activity, which represents secreted and cell-associated IL-1, was enhanced in LPS-stimulated mononuclear cultures by HF. In the absence of LPS, the initial activation product of HF, HFa, which contains the serine protease enzyme activity and the surface-binding domains of the protein, induced IL-1 beta protein and mRNA. In the presence of LPS, the enzymatic moiety (HFf), which is also contained in HF and HFa, amplified IL-1 production. Induction and amplification of monocyte IL-1 by HF provides further evidence for establishing a role for HF in the acute-phase reaction and the cellular immune response.

Enzyme Activation↗
PubMed1977

Significance of Hageman factor (coagulation factor XII) for neutrophil locomotion and chemotaxis.

Neutrophils separated from Hageman factor-deficient blood exhibit normal random and directional locomotion. No defect in cytotaxin formation could be demonstrated in Hageman factor-deficient plasma, nor did kallikrein inhibitor interfere with the chemotactic activity of normal immune complex-activated human plasma. The results suggest that the chemotactic activity which is detectable in unfractionated human plasma is not derived from Hageman factor-dependent pathways.

Antigen-Antibody Complex↗
PubMed1982

Classic gout in Hageman factor (Factor XII) deficiency.

A 62-year-old man with a typical history of gout was admitted to the hospital with left-sided hemiplegia. His serum uric acid level was 10.3 mg/dL, his partial thromboplastin time was 198 s, and his Hageman factor (factor XII) coagulant activity and antigen were less than 1% of normal. Aspiration of synovial fluid from his inflamed knee disclosed urate crystals and abundant leukocytes but an absence of Hageman factor antigen. The presence of acute gouty arthritis in a patient with Hageman trait challenges the role of Hageman factor in the pathogenesis of gouty arthropathy.

Extremities↗
PubMed1993

The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. In vivo use of a monoclonal anti-factor XII antibody to block contact activation in baboons.

The hypotension and disseminated intravascular coagulation (DIC) in bacteremia is thought to be mediated by the combined actions of cytokines, prostaglandins, and complement. The contact system, via the release of bradykinin and the activation of Factor XI, has been postulated to be contributing to the observed hypotension and DIC. Using a mAb to Factor XII (C6B7), we blocked the activation of the contact system in an established experimental baboon model in which Escherichia coli was infused to produce lethal bacteremia with hypotension. The untreated group (n = 5) displayed contact activation, manifested by a significant decrease in high molecular weight kininogen (HK) and a significant increase in alpha 2 macroglobulin-kallikrein complexes (alpha 2M-Kal). The C6B7-treated group (n = 5) showed an inactivation of Factor XII and the changes in HK and alpha 2M-Kal complexes were prevented. Both groups developed DIC manifested by a decrease in platelet, fibrinogen, and Factor V levels. The untreated group developed irreversible hypotension. The treated group experienced an initial hypotension that was reversed and extended the life of the animals. This study suggests that irreversible hypotension correlates with prolonged activation of the contact system, and specific antibody therapy can modulate both the pathophysiological and biochemical changes.

Animals↗
PubMed2006

Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis.

Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, indicating FXII is not required for hemostasis. We demonstrate that deficiency or inhibition of FXII protects mice from ischemic brain injury. After transient middle cerebral artery occlusion, the volume of infarcted brain in FXII-deficient and FXII inhibitor-treated mice was substantially less than in wild-type controls, without an increase in infarct-associated hemorrhage. Targeting FXII reduced fibrin formation in ischemic vessels, and reconstitution of FXII-deficient mice with human FXII restored fibrin deposition. Mice deficient in the FXII substrate factor XI were similarly protected from vessel-occluding fibrin formation, suggesting that FXII contributes to pathologic clotting through the intrinsic pathway. These data demonstrate that some processes involved in pathologic thrombus formation are distinct from those required for normal hemostasis. As FXII appears to be instrumental in pathologic fibrin formation but dispensable for hemostasis, FXII inhibition may offer a selective and safe strategy for preventing stroke and other thromboembolic diseases.

Animals↗