Factor XII-induced fibrinolysis: studies on the separation of prekallikrein, plasminogen proactivator, and factor XI in human plasma.
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Animals↗
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Activated partial thromboplastin time and minor coagulopathies.
Five commercially available activated partial thromboplastin time (APTT) test systems were compared with the kaolin partial thromboplastin time (KPTT) method to determine sensitivity in detecting minor coagulation defects. All reagent systems detected severe factor VIII-, IX-, and XI-deficient hemophilia. Homozygous states of factor XII deficiency, Fletcher factor deficiency, and high-molecular-weight kininogen deficiency (Fitzgerald trait) also showed abnormally long APTTs by all systems. Of 19 samples from patients with deficiencies of factors XII, VIII, IX, XI, and II ranging from 2.5 to 52%, eight had deficiencies that were not detected by reagent A (ellagic acid); two, by reagent B (ellagic acid); two, by reagent C (kaolin); one, by reagent D (silica); one, by the KPTT method. All deficiencies were detected by reagent E (celite). Heparin effect on plasma was less well detected by reagent A (ellagic acid) than with the other test systems. APTT test systems can vary greatly in their abilities to detect minor coagulation abnormalities.
Adult↗
Depression of factor XII-dependent fibrinolytic activity in survivors of acute myocardial infarction at risk of reinfarction.
Defective fibrinolysis may constitute a risk for the development of myocardial infarction in patients with ischaemic heart disease. We studied prospectively the factor XII-dependent plasminogen proactivator system in 49 survivors of an acute myocardial infarction. Blood samples were collected 8 weeks after hospital discharge. The factor XII-dependent fibrinolytic activity in the specimens was determined on fibrin plates after complete immuno-inhibition of the urokinase-like and the t-PA related fibrinolytic systems. During the subsequent follow-up period of 2.4 years, 10 patients developed recurrent myocardial infarction, whereas the remaining 39 patients did not. The reinfarction group of patients had a significantly lower median factor XII-dependent fibrinolytic activity (24.9 blood activating units (BAU).ml-1) than the patients without a relapse (41.9 BAU.ml-1, P < 0.02). Plasma concentrations of factor XII did not deviate significantly between the groups (P > 0.05), whereas the median plasma concentrations of prekallikrein was slightly lower in the reinfarction group (90%) than in the non-reinfarction group of patients (105%, P < 0.02). These observations point to an association between a depressed factor XII-dependent fibrinolytic activity and an enhanced risk of reinfarction in patients with a previous episode of acute myocardial infarction.
Cholesterol↗
Identification and characterization of the plasma kallikrein-kinin system inhibitor, haemaphysalin, from hard tick, Haemaphysalis longicornis.
The plasma kallikrein-kinin system inhibitor, haemaphysalin, from the hard tick, Haemaphysalis longicornis, was identified. It was found that haemaphysalin inhibited activation of the plasma kallikrein-kinin system by interfering with reciprocal activation between factor XII and prekallikrein. It did not, however, inhibit amidolytic activities of factor XIIa and kallikrein. Direct binding assay indicated that factor XII/XIIa and high molecular weight kininogen (HK) are the target molecules of haemaphysalin, and that Zn2+ ions are involved in the interactions of haemaphysalin with these target molecules. This suggests that haemaphysalin interacts with target molecules by recognizing their conformational changes induced by Zn2+ ions. Furthermore, haemaphysalin interacted with the fibronectin type II domain and domain D5, the cell binding domains of factor XII and HK, respectively. This finding suggests that haemaphysalin interferes with the association of factor XII and the prekallikrein-HK complex with a biologic activating surface by binding to these cell-binding domains, leading to inhibition of the reciprocal activation between factor XII and prekallikrein.
Animals↗
Blood plasma contact activation on silicon, titanium and aluminium.
In the present work, blood plasma protein deposition to spontaneously air oxidized silicon, titanium and aluminium was re-investigated in vitro. Immunological- and null ellipsometry methods were used to detect and quantitate adsorbed proteins, RIA methods to study the retention of preadsorbed 125I-HSA upon exposure to buffer or blood plasma, and kallikrein-specific colorimetric substrate S-2302 to follow the surface generation of kallikrein. The results show that the contact activation of coagulation and complement systems are connected on Si and Ti, but not on Al, via coagulation factor XII. Preadsorbed 125I-HSA was most readily displaced on silicon, followed by titanium and aluminium. The surfaces displayed different antibody binding patterns after short and long-time exposures to plasma. Titanium and silicon bound anti-HMWK after 1 min in plasma, but aluminium did not. When the plasma incubation time was prolonged up to 2h the anti-HMWK binding disappeared totally on titanium and decreased on silicon. During the same time period, anti-C3c binding increased to the three types of surfaces. Also, the anti-C3c binding onto Si and Ti, but not Al, disappeared after incubation in Factor XII deficient plasma or when a specific coagulation factor XII (Factor XII) inhibitor, corn trypsin inhibitor (CTI) was added to normal plasma. The surface contacted plasmas cleaved the kallikrein-specific reagent S-2302 both after single surface contact, and after reincubation of surfaces in fresh plasma. The results show that C3b and Factor XIIa and their degradation products were retained at the surfaces.
Adsorption↗
Acquired antibody to factor XI in a patient with congenital factor XI deficiency.
The results of studies in a patient with congenital deficiency of Factor XI who developed an inhibitor are presented. The patient presented with a severe, apparently spontaneous bleed into the thigh, which progressed despite infusion of fresh frozen plasma, but which responded promptly to activated prothrombin complex. During therapy with plasma his clotting time and Factor XI level were unresponsive and a Factor XI inhibitor titer of 6,000 U/ml was attained. The inhibitor was isolated and found to be polyclonal immunoglobulin G (IgG), predominantly of subclass 4. The specificity of the antibodies for Factor XI was shown by the ability of isolated inhibitor bound to polyacrylamide beads to remove Factor XI selectively from normal plasma. The binding of (125)I-labeled factor XI to the inhibitor was studied and an affinity constant of 1.65 x 10(10) liter/mol was found. Complexing of the antibodies with Factor XI was shown to block multiple activities of the clotting factor. Factor XI complexed with antibody did not bind to high molecular weight kininogen or undergo activation and cleavage by two-chain Factor XII. The complex of activated Factor XI with inhibitor prevented the cleavage and activation of Factor IX. Hence the inhibitor appears to act by binding to multiple sites on the Factor XI molecule and preventing its interaction with other molecules. Clinically these interactions of the inhibitor with Factor XI result in a state of severe Factor XI deficiency. The clinical circumstances of the case, with severe hemorrhage refractory to plasma infusion but readily responsive to an alternate clot-promoting agent, suggest that a defect of intrinsic system activation was critical, supporting the inference that Factor XI does participate in normal hemostasis. The clinical course of this patient, who has only had two documented hemorrhages in the presence of the inhibitor, is not as severe as that of patients with severe Factor VIII or IX deficiency. This suggests that physiologic activation of Factors XI and IX does not occur exclusively in series because deficiency of factors XII, XI, VIII, and IX should then have similar hemostatic consequences. We propose that independent mechanisms for bypass of Factors XII and XI are important in physiologic activation of coagulation.
Animals↗
[Activation of the antihemophilic globulin A (factor VIII). 2. Effect of ampholine on the course of blood coagulation and the molecular conformation of factor VIII].
Ampholine leads to an increase of activity of factor VIII and in vitro at the same time inhibits the activation of factor XII. The influence on factor XII takes place via influence on the contact surface. All the other coagulation factors remain uninfluenced. There are no differences between normal plasma and plasma of haemophilia with regard to the influence by ampholine. The molecular weight of factor VIII remains uninfluenced by ampholine. The activity of the various molecular forms of factor VIII is increased at the same level by ampholine.
Ampholyte Mixtures↗
New and old cardiovascular risk factors: C-reactive protein, homocysteine, cysteine and von Willebrand factor increase risk, especially in smokers.
BACKGROUND: The relative importance of new risk factors for heart disease singly or in combination is uncertain. We assessed relationships between C-reactive protein, homocysteine, cysteine, von Willebrand factor, activated factor XII and stable heart disease, as well as interaction with established risk factors. METHODS: A case-control study of 260 cases of stable heart disease from the Irish component of the European Action on Secondary Prevention through Intervention to Reduce Events (EUROASPIRE) II cohort and 260 age, sex-matched controls. C-reactive protein, homocysteine, cysteine, von Willebrand factor, activated factor XII and conventional risk factors were assayed or recorded. Interaction effects between new and conventional factors were assessed using additive and multiplicative models. RESULTS: C-reactive protein, homocysteine, cysteine and von Willebrand factor were significantly higher in cases than controls. Comparing the top fifth with the bottom four-fifths showed independent associations between heart disease and C-reactive protein [odds ratio (OR) 1.79; 95% confidence interval (CI) 1.12-2.86; P = 0.01], cysteine (OR 2.00; 95% CI 1.25-3.20; P = 0.004), von Willebrand factor (OR, 3.0; 95% CI 1.9-4.8; P < 0.0001). For homocysteine, the association was independent comparing the top tenth to the bottom nine-tenths (OR 1.95; 95% CI 1.02-3.41; P = 0.04). Activated factor XII was not associated with risk. The association between C-reactive protein and disease was U-shaped and a graded association existed between homocysteine, cysteine, von Willebrand factor and disease. C-reactive protein, homocysteine, cysteine and von Willebrand factor considerably increased risk associated with other factors, particularly smoking. CONCLUSIONS: Independent associations exist between stable heart disease and C-reactive protein, homocysteine, cysteine and von Willebrand factor. Strong combined effects were observed between these and conventional risk factors, particularly smoking. Smoking cessation may profoundly reduce risk associated with other risk factors. We found no evidence of a relationship between activated factor XII and disease.
Adult↗
Hageman factor and risk of myocardial infarction in middle-aged men.
In order to evaluate whether Hageman factor (XII) is increased in survivors of myocardial infarction and whether this in turn influences factor VII coagulant activity (VIIc), we examined the coagulation and lipoprotein profiles in 82 subjects, 51 of whom had a definite history of myocardial infarction and 31 healthy volunteers invited from a local general practice register for a cardiovascular screen. Both serum cholesterol (P = 0.03) and plasma fibrinogen levels (P = 0.02) were significantly elevated in cases compared with controls. There were no significant differences in coagulant activities, and in particular factor XII concentration was not significantly different between groups. Furthermore, in 47 of the subjects, 28 of whom had a history of myocardial infarction, a more detailed analysis, including measurement of VIIc after overnight incubation of plasma at 4 degrees C, was undertaken. Approximately half the subjects in either group showed some evidence of activation, though history of myocardial infarction was not in itself a significant predictor of this. All measures of XII concentration related positively to VIIc after cold activation, the strongest being the measure of amidolytic activity following activation of factor XII (XIIAm) (r = 0.5, P < 0.01). In addition, XIIa, a measure of activity due to enzymes derived from factor XII, related strongly to many of the measured lipoprotein variables, particularly VLDL cholesterol and triglycerides, supporting the hypothesis that negatively charged molecules such as free fatty acids on larger lipoprotein particles provide the contact surface necessary to activate factor XII. The findings confirm the importance of this alternative pathway in leading to activation of factor VII.
Aged↗
The sympathoadrenal system mediates the blood pressure and cardiac effects of human coagulation factor XII-related "new pressor protein".
OBJECTIVE: To investigate the major cardiovascular effects of human plasma "new pressor protein" (NPP) and how the adrenal medulla contributes to these effects. METHODS: NPP was injected into bioassay rats intravenously, and the effects on blood pressure and cardiac function were investigated. Acute adrenal medullectomy (2MDX), alpha- and beta-adrenergic blockade and plasma catecholamine levels were also used to evaluate the role of the sympathoadrenal system in mediating the NPP effects. RESULTS: NPP significantly raised systolic blood pressure (SBP) and mean arterial pressure but not diastolic blood pressure (DBP), with no significant change in total peripheral resistance. Heart rate, cardiac output and stroke volume rose by 16%, 53% and 36%, respectively. Plasma catecholamines increased massively, notably adrenaline, raising the adrenaline to noradrenaline ratio from about 4:1 to 18:1. 2MDX attenuated the increments of SBP and heart rate by more than 90% and more than 70%, respectively, implicating the adrenal medulla. Beta-adrenergic blockade (propranolol) potentiated the NPP-induced increase of SBP and DBP, but not that of heart rate. Combined alpha- and beta-adrenergic blockade (phentolamine and propranolol) blocked the rise in SBP, DBP and heart rate. CONCLUSIONS: NPP's hypertensive action is attributable mainly to increases in systolic blood pressure, heart rate and cardiac output (an increase in heart rate and stroke volume) with massive release of adrenal medullary catecholamines. Such effects suggest a novel axis between coagulation factor XII and the sympathoadrenal system, the cardiovascular effects of which are controlled by combined alpha- and beta-adrenergic blockade, but not by angiotensin-converting enzyme inhibition. Clinical relevance depends on whether NPP is formed in vivo in thrombotic states.
Angiotensin-Converting Enzyme Inhibitors↗
Preparation of beta-XIIa (Hageman factor fragment) from human plasma.
beta-Factor XIIa (beta-XIIa, Mr approximately 30,000) was isolated from human plasma by a procedure which utilized, as an initial step, the adsorption of Factor XII to celite. Activation of Factor XII and subsequent release of beta-XIIa was brought about by the proteolytic action of co-adsorbed kallikrein. Two successive chromatographic procedures were then used to achieve a final purification of 4,420-fold over plasma and an overall field of 2.3 mg of beta-XIIa per liter.
Adsorption↗
Activation of arginine and tyrosine esterase in serum from patients with hereditary angio-oedema.
1. The role of clotting factor XII in the activation of the complement subunit C1s to C1 esterase was examined.2. In sera from patients with hereditary angio-oedema who lack the alpha(2)-glycoglobulin C1 inhibitor, silicates and other potent activators of clotting factor XII induced far less C1 esterase activity than did the weaker factor XII activators, carrageenin and cellulose sulphate. In contrast, the intensity of the induced plasma kallikrein activity corresponded more closely to the clot-promoting effect of the factor XII activators.3. Spontaneous generation of C1 esterase activity was only slightly delayed in hereditary angio-oedema sera previously depleted of factor XII. In normal sera, C1 esterase did not develop spontaneously and could not be induced.4. Experiments with inhibitors suggested that the spontaneous activation of C1s may consist of two phases: factor XII and other plasma proteases first activate small amounts of C1s; the resulting C1 esterase then activates the bulk of C1s. The observed spontaneous activation suggests that when fully activated, the C1s present in 1 ml of human serum will hydrolyse 1-2 mumol of ATEe/minute.
Angioedema↗
Contact phase of blood coagulation in diabetes mellitus.
The first phase of the intrinsic coagulation system was studied in twenty-six diabetic outpatients. The parameters tested were kallicrein, prekallicrein, factor XI and factor XII activities. Kallicrein and factor XI showed significantly elevated activities as compared with a normal control group (P less than 0.05 and less than 0.001, respectively). Factor XI and factor XII levels were higher in non-insulin dependent than in insulin dependent diabetics. We found that the kallicrein-prekallicrein system was activated in our diabetic patients and that such activation could probably be secondary to lesions of the vascular endothelium present in long-term diabetics. No correlation was found between glycaemia and activity levels of this system. Our data represent another demonstration of the existence of a hypercoagulable state in diabetes mellitus.
Adult↗
Analysis of intrinsic fibrinolysis in human plasma induced by dextran sulfate.
The analysis of normal human plasma by fibrin autography revealed four species of plasminogen activator (PA) activity related to tissue-type PA, factor XII, prekallikrein and urokinase-type PA (u-PA). The u-PA activity increased significantly by incubating plasma with dextran sulfate. This increase was coincident with both the cleavage of factor XII and the complex formation of activated factor XII with its plasma inhibitors, which were determined by immunoblotting procedure. The dextran sulfate-dependent activation of u-PA required both factor XII and prekallikrein, but did not require either plasminogen or factor XI. High molecular weight kininogen was required only at a low concentration of dextran sulfate. Thus the results indicate that the factor XII and prekallikrein-mediated activation of single chain u-PA (scu-PA) operates as a major pathway of scu-PA activation in whole plasma in contact with dextran sulfate.
Dextran Sulfate↗
Long-lasting depression of the factor XII-dependent fibrinolytic system in patients with myocardial infarction undergoing thrombolytic therapy with recombinant tissue-type plasminogen activator: a randomized placebo-controlled study.
In a randomized placebo-controlled study, seven patients with acute myocardial infarction allocated to intravenous treatment with 100 mg of recombinant tissue-type plasminogen activator (rt-PA) and seven patients allocated to placebo were studied during eight sampling periods before and after treatment. Seven patients with acute myocardial infarction treated intravenously with 1.5 million U of streptokinase were later studied during two sampling periods before and after treatment. The placebo group showed no significant deviations of endogenous factor XII-dependent fibrinolytic activity (p greater than 0.05). In the rt-PA group, this activity decreased significantly (p less than 0.001) after the infusion and remained depressed throughout the 1st 4 days. A significant decrease in activity (p less than 0.05) was also found in the streptokinase-treated patients. The depletion of factor XII-dependent fibrinolytic activity was not due to generation of inhibition or a depletion of factor XII, prekallikrein and plasminogen, but could be related to the proactivator of this system. It is concluded that rt-PA (and streptokinase) treatment in patients with acute myocardial infarction causes a prolonged depletion of factor XII-dependent fibrinolytic activity. This depression of endogenous fibrinolytic activity needs to be evaluated in relation to the enhanced risk of coronary reocclusion after thrombolytic therapy.
Depression, Chemical↗
Characterization of bovine factor XIIa (activated Hageman factor).
Factor XIIa (activated Hageman factor) was isolated from bovine plasma by ammonium fractionation followed by heparin-agarose, carboxymethylcellulose, and arginine-agarose column chromatography. It was separated from factor XII in the final step by chromatography on benzamidine-agarose. Factor XIIa has a molecular weight of approximately 74 000 and is composed of a heavy and light chain held together by a disulfide bond(s). The amino-terminal sequence of the heavy chain is Thr-Pro-Pro-Trp--Lys-Gly-Pro-Lys-Lys-His-Lys-Leu- which is the same as the precursor protein. The carobyl-terminal residue in this polypeptide chain is arginine. The amino-terminal sequence of the light chain is Val-Val-Gly-Gly-Leu-Val-Ala-Leu-Pro-Gly-Ala-?-Pro-Tyr-Ile-. This latter sequence is homologous with the amino-terminal sequence of a number of plasma serine proteases when compared with the chain containing the active-site serine residue. These data suggest that factor XII is converted to factor XIIa by the cleavage of a specific internal arginyl-valine peptide bond. Factor XIIa, in contrast to factor XII, has hydrolase activity toward arginine-containing substrates and is readily inhibited by antithrombinIII and diisopropyl phosphorofluoridate. The inhibitors, in each case, are bound to the light chain of factor XIIa which contains the active-site serine residue.
Amino Acid Sequence↗
Dextran-induced anaphylactoid reaction in man: altered reactivity of high molecular weight kininogen.
Normal levels of factor XII and of high and low molecular weight kininogens (HMWK and LMWK) were registered in plasma specimens from 5 individuals who had developed anaphylactoid reactions upon injection of dextran during surgery (dextran reactors, DR). Factor XII was assayed as prekallikrein activator (PKA) activated with kaolin at 0 degrees, and kininogen fractions were estimated through the release of kinin caused by plasma kallikrein or hog pancreas kallikrein (HPK). Subnormal levels of factor XII apparently present in plasma from one DR, and after affinity chromatography on a lysine-Sepharose column also in plasma from another DR, were normalized by addition of plasma deficient in factor XII or by addition of purified HMWK. Treatment of plasma from DR with acetone (25% v/v) induced a conversion of HMWK into a state which was non-functional as a cofactor in the surface-dependent activation of factor XII, and the passage of plasma from DR through a lysine-Sepharose column altered the HMWK present to a substance that released kinin only very slowly by incubation with HPK. It is concluded that the treatments mentioned will favour the activation in plasma from DR of a factor that will cause the conversion of HMWK. Previous experiments with rat plasma demonstrated that plasmin and also a plasmin-like factor without affinity for lysine-Sepharose were able to destroy the capacity of HMWK to function as a cofactor in the surface-dependent activation of factor XII, without a corresponding release of kinin.
Adult↗
John Hageman's factor and deep-vein thrombosis: Leiden thrombophilia Study.
Because the relationship between factor XII deficiency and venous thrombosis is unclear and study results seem contradictory, we undertook a population-based case-control study. Among 350 unselected patients younger than 70 years, with a first, objectively confirmed, episode of deep-vein thrombosis and without underlying malignant disease we detected a 6% frequency (21/350 patients) of factor XII deficiency (activity level < 57%). Among 350 healthy control subjects, matched for age and sex, the frequency was 5% (18 subjects). Thus there is no increase in prevalence of factor XII deficiency among thrombosis patients and no increase in thrombosis risk for subjects with low factor XII levels (matched odds ratio 1.2 (95% CI 0.6-2.4)). In addition, there was no relation between strata of factor XII levels and thrombosis risk. In conclusion, we do not consider factor XII to be a determinant of deep-vein thrombosis.
Adolescent↗