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PubMed1978

Human platelet chemotaxis: requirement for plasma factor(s) and the role of collagen.

Platelets are actively mobile in plasma in vitro and, in addition, they migrate specifically and directionally toward added intact collagen (chemotaxis). Native human, bovine, and equine collagen, suspended in plasma, induce a chemotactic response in human platelets. However, heat-denatured and dinitrofluorobenzene-treated collagen fail to attract platelets. Platelets migrate directionally and specifically to intact native collagen incubated in plasma over a large distance (6 mm) in a very short time (total 15 min), as observed in a newly designed micromaze apparatus. Platelets obtained from donors deficient in plasma factors XII, IX, and VIII showed normal migration and chemotaxis in normal plasma and in their respective factor-deficient plasmas. Although nondirectional movement (mobility) was normal, platelets from a donor deficient in factor XI did not exhibit chemotaxis toward collagen in either factor XI-deficient plasma or in normal plasma. The results indicate that 1) collagen is a physiological substrate for the chemotactic phenomenon, 2) intact chemical and/or structural integrity of collagen is required for the induction of platelet chemotaxis, 3) at least one plasma constituent, factor XI, plays an essential role in the chemotactic phenomenon, and 4) contact between collagen and a plasma factor is essential for normal chemotaxis.

Blood Platelets↗
PubMed1988

Combined factors IX and XII deficiencies in a family of cats.

Combined factors IX and XII deficiencies were detected in a family of cats in which 2 male kittens had bleeding diathesis. The combination of factors IX and XII deficiencies in one male kitten did not appear to exacerbate bleeding when compared with a sole deficiency of factor IX in its male sibling. Neutering of carrier females and affected males was recommended. Blood transfusions before castration of affected males was advised.

Animals↗
PubMed1968

Activation of Hageman factor by collagen.

Purified acid-soluble and insoluble human collagen accelerated the clotting of plateletpoor plasma in silicone-treated tubes. The clot-promoting effect did not appear to be due to thromboplastic activity since the collagen preparations did not activate factor X in the presence of factor VII and calcium. Instead, collagen appeared to accelerate clotting by activating Hageman factor (factor XII) on the basis of the following findings: collagen increased the clot-promoting activity of partially purified Hageman factor but exerted no further effect in the presence of kaolin, a known activator of Hageman factor; clot-promoting eluates were obtained from collagen exposed to normal, hemophilic, or PTC-deficient plasma but not from collagen exposed to Hageman or PTA-deficient plasma. The collagen molecule itself appeared to be required for the clot-promoting activity since digestion with collagenase or thermal denaturation at pH 2.5 (about 35 degrees C) resulted in very marked reduction in clot-promoting activity. Since thermal denaturation is associated with transformation of collagen structure from triple helical to random coil form, it is suggested that the native form of collagen is essential for the ability to activate Hageman factor. Blockage of the free amino groups by treatment with nitrous acid or dinitrofluorobenzene only slightly reduced the clot-promoting activity of collagen. In contrast, since addition of cationic proteins to collagen markedly reduced pro-coagulant activity it is suggested that negatively charged sites on the collagen molecule are critical for Hageman factor activation. This suggestion is supported by the finding that pepsin treatment of collagen, which removes the predominantly negatively charged telopeptides, results in significant decrease in coagulant activity. Esterification of collagen, which neutralizes 80-90% of the free carboxyl groups, reduced coagulant activity by over 90% and it is suggested that the free carboxyl groups of glutamic and aspartic acids provide the negatively charged sites critical for Hageman factor activation.

Adult↗
PubMed1991

Abnormal proteolytic degradation of von Willebrand factor after desmopressin infusion in a new subtype of von Willebrand disease (ID).

We describe two members of a single family, father and son, with mild factor XII deficiency associated to von Willebrand disease (vWD) with aberrant structure in whom distinct multimeric abnormalities and an abnormal proteolytic processing of von Willebrand factor (vWF) after desmopressin (DDAVP) administration were present. They had a mild bleeding history, low levels of vWF-related activities, and a prolonged bleeding time. Low-resolution agarose gel electrophoresis showed a vWF with all size multimers in plasma and platelets. Higher-resolution agarose gels demonstrated that the main band was present, but the relative proportion of the satellite bands was markedly reduced. The smallest oligomer was not increased. After the infusion of DDAVP to the father, a transient increase in the relative proportion of the satellite bands was seen, as described in normal individuals. No difference in the structure of vWF was observed when blood was collected with proteinase inhibitors. The analysis of native subunits of vWF and their proteolytic derived fragments, after DDAVP administration, showed a temporary augmentation of the 176 kDa fragment, as seen in normal subjects, as well as an increase of the 189 kDa fragment. This finding had not been reported previously either in normal individuals or in patients with vWD.

Adult↗
PubMedDate not supplied

[Adsorption properties of Beidellite (author's transl)].

The beidellite is both an activator and an adsorbing agent for certain clotting factors: at low concentration (1 p. 1 000), factors XII and VII of human plasma are activated. At a concentration of 10 p. 1 000, the fibrinogen is totally adsorbed, leaving in the supernatant most of the VIII. At alpha 20 p. 1 000 concentrations, most of factor II remains unabsorbed, the remaining plasma being devoided of other clotting factors except minute amounts of factors XI and XII. Contrarely to bentonite, which has similar properties, beidellite does not absorb water and does not modify the pH. Beidellite is therefore a very useful agent for selective adsorption of clotting factors.

Adsorption↗
PubMed1979

Amidolytic properties of single-chain activated Hageman factor.

Activation of Hageman factor (Factor XII) upon exposure to negatively charged agents has been attributed to proteolytic cleavage of this molecule. To examine this question, purified Hageman factor was exposed to Sephadex gels to which ellagic acid had been adsorbed. Such Hageman factor, separated from the gels and studied in the fluid phase, was amidolytic. Nonetheless, no cleavage of Hageman factor treated in this way could be demonstrated by sodium dodecyl sulfate/polyacrylamide gel electrophoresis. Thus, activation of Hageman factor by negatively charged agents was not necessarily accompanied by molecular scission.

Amidohydrolases↗
PubMed1969

Studies on a complex mechanism for the activation of plasminogen by kaolin and by chloroform: the participation of Hageman factor and additional cofactors.

As demonstrated by others, fibrinolytic activity was generated in diluted, acidified normal plasma exposed to kaolin, a process requiring Hageman factor (Factor XII). Generation was impaired by adsorbing plasma with glass or similar agents under conditions which did not deplete its content of Hageman factor or plasminogen. The defect could be repaired by addition of a noneuglobulin fraction of plasma or an agent or agents eluted from diatomaceous earth which had been exposed to normal plasma. The restorative agent, tentatively called Hageman factor-cofactor, was partially purified by chromatography and had an apparent molecular weight of approximately 165,000. It could be distinguished from plasma thromboplastin antecedent (Factor XI) and plasma kallikrein, other substrates of Hageman factor, and from the streptokinase-activated pro-activator of plasminogen. Evidence is presented that an additional component may be needed for the generation of fibrinolytic activity in mixtures containing Hageman factor, HF-cofactor, and plasminogen.The long-recognized generation of plasmin activity in chloroform-treated euglobulin fractions of plasma was found to be dependent upon the presence of Hageman factor. Whether chloroform activation of plasminogen requires Hageman factor-cofactor was not determined, but glass-adsorbed plasma, containing Hageman factor and plasminogen, did not generate appreciable fibrinolytic or caseinolytic activity. These studies emphasize the complex nature of the mechanisms which lead to the generation of plasmin in human plasma.

Blood Coagulation Factors↗
PubMed1983

Factors XI and XII are low in subjects with liver disease.

We prospectively measured levels of factors XI and XII in parallel with other coagulation factors in 39 unselected patients with liver disease and in 20 control subjects. Mean levels of factors XI and XII in subjects with liver disease were significantly reduced, being 58% and 61%, respectively, compared with 100% and 94% in controls. Reductions in levels of factors XI and XII were most pronounced in those subjects with low serum albumin. The partial thromboplastin time (APTT) reflected low levels of either factor XI or XII and was most prolonged when both were low, but cause and effect was not demonstrated. Low levels of these factors may explain previous reports of poor response of APTT to infusions of prothrombin complex concentrates. Finally, these low levels strongly suggest that factors XI and XII are produced in the liver.

Blood Coagulation Factors↗
PubMed1984

Asbestos-related fibrin formation in human plasma.

This study was designed to test the hypothesis that asbestos is responsible for the activation of clotting, for the reduction in activity of clotting factors and for the formation of fibrin when human plasma is exposed to asbestos chrysotile fibers in vitro. The recalcification time was accelerated in the early phase and was found to be greatly prolonged at 24 hours. The activated partial thromboplastin time showed marked changes at 24 hours only. One group of clotting factors, consisting of factors V, IX and X, showed the greatest decrease in their plasmatic activity. The factors least changed were factors XII and VIII; the other clotting factors were found in between these groups. Histologic examination demonstrated fibrin fibers in close proximity to the asbestos. Thus, chrysotile asbestos fibers activate clotting with the subsequent decrease in activity of some coagulation factors resulting in the formation of fibrin.

Adult↗
PubMed1998

Newer concepts of blood coagulation.

In this report we describe an in vitro model of blood coagulation reactions that mimics as closely as possible the in vivo condition. Our model indicates that the tissue factor-factor VIIa complex initiates coagulation by activating small amounts of both factor IX and factor X in the environment of the tissue factor bearing cell. Factor Xa and factor IXa formed in the initial reaction then play very distinct roles in the subsequent interactions of the clotting mechanism leading to a burst of thrombin generation on the platelet surface. Our results also indicate that factor XI can be activated by thrombin in the absence of factor XII and that the function of factor XI is simply to enhance conversion of factor IX to factor IXa resulting in enhanced thrombin generation on the platelet surface.

Animals↗
PubMed1999

The role of factor XI in coagulation: a matter of revision.

In 1991 it was demonstrated that, besides factor XII, thrombin is capable of activating factor XI in vitro. Thrombin-dependent activation of factor XI is an integral part of the revised theoretical model of coagulation in which coagulation is initiated by the extrinsic pathway and maintained by thrombin-induced activation of clotting factors V, VIII, and XI. In this review, special interest is given to the new role of factor XI in coagulation, with emphasise on data supporting the concept of thrombin-mediated factor XI activation in vivo. Furthermore, activation of factor XI in human disease, especially atherosclerotic disease, measured by newly developed immunologic assays, is discussed. The relation of factor XI to fibrinolysis through activation of the carboxypeptidase, thrombin-activatable fibrinolysis inhibitor (TAFI) by thrombin provides an explanation for the bleeding tendency observed in factor XI-deficient patients. The probable link with factor XI-mediated TAFI activation may have clinical and therapeutic consequences and deserves further study.

Arteriosclerosis↗
PubMed2001

Plasma levels of factor XIIa and factor VIIa are increased but not related in primary hyperlipidaemia.

The lipolysis of triglyceride-rich lipoproteins may provide a surface that supports the activation of factor XII (FXII) with subsequent activation of factor VII (FVII). Plasma levels of activated FVII (FVIIa) but not activated FXII (FXIIa) are increased in the post-prandial state when there is a transient increase in triglyceride levels. We compared plasma levels of FXIIa antigen in control subjects (n = 33) and in patients with chronically elevated lipids (primary hyperlipidaemia, n = 49), with FVIIa and markers of thrombin generation. Results are given as median (first and third quartiles). Plasma levels of FXIIa [2.34 (1.68-3.32) ng/ml versus 1.53 (0.93-1.86) ng/ml, P = 0.0002], FVIIa [3.02 (2.15-4.64) ng/ml versus 2.20 (1.66-2.56) ng/ml, P = 0.0004], thrombin-antithrombin complexes [3.08 (2.16-5.54) microg/I versus 2.13 (1.46-2.84) microg/l, P = 0.005] and prothrombin fragment 1 + 2 (Pro F1 + 2) [1.28 (1.08-1.50) nmol/l versus 0.92 (0.65-1.08) nmol/l, P = 0.0001] were increased compared with controls irrespective of the type of hyperlipidaemia. In hyperlipdaemic subjects, levels of Pro F1 + 2 were correlated with FVIIa (r = 0.56, P = 0.0002) and FXIIa (r = 0.31, P = 0.03). These results suggest increased activation of both FVII and FXII in hyperlipidaemic subjects, which correlates with increased thrombin generation. Given the lack of correlation between levels of FXIIa and FVIIa, it remains to be established whether the increase in FXIIa is responsible for increased FVIIa activity in this subject group.

Adult↗
PubMed2000

Contact activation in shock caused by invasive group A Streptococcus pyogenes.

OBJECTIVES: The aim of this study was to characterize abnormalities of coagulation in mice with experimental, invasive group A, streptococcal shock, in an attempt to explain the prolongation of the activated partial thromboplastin time identified in patients with streptococcal toxic shock syndrome. DESIGN: A longitudinal descriptive animal model study of coagulation times and single coagulation factors in mice infected with Streptococcus pyogenes. This was followed by an experimental study to determine whether streptococci or streptococcal products could activate the human contact system in vitro. SETTING: University infectious diseases and hemostasis molecular biology laboratories. SUBJECTS: CD1 outbred mice. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Coagulation times, single factor assays, and bradykinin assays were conducted on murine plasma at different times after streptococcal infection and compared with uninfected mice. In experiments in which streptococcal products were co-incubated with human plasma, we compared coagulation times, single factor assays, and activities against a range of chromogenic substrates with control plasma. In a murine model of streptococcal necrotizing fasciitis, the activated partial thromboplastin times were significantly prolonged in infected mice compared with controls, whereas prothrombin times were normal, suggesting an isolated abnormality of the intrinsic pathway. Bleeding was not seen. Prolongation of activated partial thromboplastin time was associated with reduced factor XII and prekallikrein, whereas levels of factors VIII, IX, XI, and high molecular weight kininogen were elevated. In vitro studies suggested that streptococcal supernatants can activate prekallikrein, in addition to causing plasminogen activation through the action of streptokinase. CONCLUSIONS: Prolongation of activated partial thromboplastin time in streptococcal toxic shock syndrome is associated with activation of the contact system, possibly contributing to the profound shock associated with streptococcal toxic shock syndrome.

Animals↗
PubMedDate not supplied

Collagen type III induced ex vivo thrombogenesis in humans. Role of platelets and leukocytes in deposition of fibrin.

Exposure of type III collagen coats on plastic cover slips in parallel-plate perfusion chambers to flowing nonanticoagulated human blood resulted in deposition of platelets and fibrin. Blood was drawn directly from an antecubital vein by an occlusive roller pump over the collagen coats in chambers having flow slits of different dimensions, so that wall shear rates of 100, 650, and 2600 s-1 were obtained at 10 ml/min. Coagulation was minimally activated during the passage of blood from the vein to the chamber as shown by fibrinopeptide A levels of 3.7 ng/ml after 5-minute perfusions. The surface coverage with platelets increased from 18% at 100 s-1 to 59% at 2600 s-1, and the corresponding thrombus volumes increased from 2 to 22 microns 3/microns 2, respectively. This contrasted with the coverage with fibrin on collagen, which decreased from 28% at 100 s-1 to 9% at 2600 s-1. Fibrin deposits on the thrombi covered 6% of the surface irrespective of the shear rate, indicating that some of the deposited platelets accelerated the deposition of fibrin. The type III collagen preparation did not activate factor XII and did not possess tissue factor activity, indicating that the surface itself was not procoagulant. However, a correlation between deposited leukocytes and surface coverage with fibrin was observed (r = 0.78, p less than 0.01), suggesting a role for these cells in the deposition of fibrin. The data demonstrate that thrombogenesis is triggered by pure type III collagen, although the deposition of fibrin is not initiated by the collagen itself but presumably by deposited leukocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Coagulation↗
PubMed1988

Induction of fibrinolysis by polyanions in human plasma.

The fibrinolytic potency of several polyanions was comparatively investigated. Fibrinolytic activity was measured in a whole plasma assay using H-D-Val-Leu-Lys-pNA (S-2251) as chromogenic substrate and by a fibrin plate assay using plasminogen rich fibrin plates. In the chromogenic substrate assay potent fibrinolytic polyanions comprised dextran sulfate, GAGPS, pentosan polysulfate, polyanethol sulfate, l-carrageenan and i-carrageenan. Chondroitin sulfates A, B, C, keratan sulfate, ribonucleic acid, k-carrageenan and heparin were weakly fibrinolytic. Hyaluronic acid and lipopolysaccharide from E. coli were inactive. Similar results were obtained when fibrinolytic activity was measured by a fibrin plate assay. All polyanions except lipopolysaccharide produced lysis zones. Induction of fibrinolytic activity in human plasma was shown to be at least partially dependent on Hageman factor. In factor XII deficient plasma no fibrinolysis was induced by any of the polyanions when measured in the fibrin plate assay. In the chromogenic substrate assay corn Hageman factor inhibitor (CHFI) inhibited the activation of S-2251 cleaving enzyme by GAGPS, pentosan polysulfate, polyanethol sulfate, heparin, and ribonucleic acid near completely. The activation by dextran sulfate was inhibited by 45%. Heparin, pentosan polysulfate and GAGPS, three polyanions of therapeutic interest were separately compared. In both assays GAGPS proved the most potent activator, while pentosan polysulfate exhibited 83% and 44% and heparin 32% and 14% of GAGPS fibrinolytic activity in the chromogenic substrate test and the fibrin plate assay, respectively.

Chromogenic Compounds↗
PubMed1996

Species differences in amino acid sequences of Hageman factor and prekallikrein at region around scissile bond in activation.

The initial step in activation of the plasma kinin system is activation of Hageman factor (coagulation factor XII) and/or plasma prekallikrein. Two types of activation mechanisms, contact activation on a negatively charged surface and a cascade activation by exogenous proteases are known. Since these factors are serine protease zymogens, the activation of these molecules usually results from the cleavage of a particular -Arg-Ile(Val)- bond in either mechanism. Hence, these zymogens are regard to be substrates of their activator proteases. Sensitivity of the substrate for the protease basically depends on the amino acid sequence of six to eight residues around the scissile bond of the substrate. We found different activation efficiencies of these zymogens between human and guinea pig in both types of activation, and micro-heterogeneity of the sequence around the scissile bond among human, guinea pig and bovine Hageman factors, or between human and guinea pig prekallikreins. The sequence heterogeneity may explain the different activation efficiencies of these zymogens among mammalian species.

Amino Acid Sequence↗
PubMed1976

Failure of tranexamic acid to influence the ellagic acid-induced hypercoagulable state.

Tranexamic acid in a dose of 50 mg/kg b.w. was unable to alter the ellagic acid induced hypercoagulable state. No change in the hypercoagulability pattern was observed regardless of the time of administration of the compound (before or after the ellagic infusion). The silicone clotting times after the infusion of ellagic acid were markedly shortened and remained so for about 60 minutes. The results observed in two control groups treated with saline were similar. The euglobulin lysis times were clearly prolonged after the administration of tranexamic acid, whereas no changes were observed after the administration of saline. These results indicate that tranexamic acid has no anti-factor XII activity.

Animals↗
PubMed2004

Homozygosity of the T allele of the 46 C->T polymorphism in the F12 gene is a risk factor for ischemic stroke in the Spanish population.

BACKGROUND AND PURPOSE: Ischemic stroke (IS) is a complex disease that involves genetic and environmental factors. In a family-based study (the Genetic Analysis of Idiopathic Thrombophilia [GAIT] Project) that included a genome-wide scan, we demonstrated that a common polymorphism (46 C-->T) in the exon 1 of the F12 gene jointly influences variability of plasma Factor XII levels and susceptibility to thrombotic disease. We have investigated the risk of IS related to this polymorphism in a case-control study. METHODS: We studied 436 individuals: 205 diagnosed with IS and 231 age-gender-ethnic control subjects. We measured Factor VIIIc, fibrinogen, and Factor XIIc levels, and we genotyped the 46 C-->T polymorphism in the F12 gene. RESULTS: There were 91 women and 114 men in the IS group and 109 women and 122 men in the control group. We confirmed our previous observation that individuals with different genotypes for the 46 C-->T polymorphism showed significant differences in Factor XIIc levels. Most importantly, the mutated T allele in the homozygous state (genotype T/T) was associated with an increased risk of IS with an adjusted odds ratio of 4.1 (95% CI, 1.1 to 15.9). CONCLUSIONS: This study suggests that the 46 C-->T polymorphism is a genetic risk factor for IS in the Spanish population. In addition, our results confirm that the use of genetic linkage studies along with a case-control association study is an extremely valuable approach for identifying DNA variants that affect complex diseases.

Adult↗