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PubMed1991

Inhibition of the activation of Hageman factor (factor XII) and of platelet aggregation by extracts of Brugia malayi microfilariae.

In human filariasis, large numbers of blood-borne microfilariae circulate unimpeded through the blood stream. How intravascular filarial parasites avoid precipitating thrombosis has not been studied in detail. We hypothesized that extracts of Brugia malayi microfilariae would contain factors that inhibit activation of hemostatic mechanisms. Initial studies demonstrated an inhibitor specific for the intrinsic coagulation cascade. The addition of microfilarial extracts to human plasma prolonged the activated partial thromboplastin time in a dose-dependent fashion but did not prolong the prothrombin, thrombin, or Russell's viper venom times. Microfilarial extracts (0.1 mg/ml) completely inhibited activation of Hageman factor (factor XII, at 0.05 U/ml) as measured in an amidolytic assay. Hageman factor previously activated by ellagic acid (factor XIIa) retained full enzymatic activity in the presence of microfilarial extract (0.1 mg/ml). The presence of inhibitory activity in the culture medium of live parasites raises the possibility that microfilariae secrete an inhibitory protein into their local environment. Microfilarial extracts at a final concentration of 0.1 mg/ml also inhibited collagen- and adenosine diphosphate-induced platelet aggregation. Arachidonic acid-induced platelet aggregation was inhibited by microfilarial extracts at a final concentration of 0.6 mg/ml. These results suggest that microfilariae of Brugia malayi, a human filarial parasite, may avoid initiating thrombosis through inhibition of the intrinsic coagulation pathway and platelet aggregation.

Adenosine Diphosphate↗
PubMed1990

Adsorption of Hageman factor (factor XII) and other human plasma proteins to biomedical polymers.

Protein adsorption to surfaces occurs whenever blood comes into contact with biomaterials, prosthetic devices, and artificial organs. The plasma protein Hageman factor (factor XII) present at the interface between blood and foreign surfaces can be qualitatively and quantitatively detected after in vitro perfusion of anticoagulated human blood through important biomedical polymers. We have determined protein adsorption by a modified radioimmunoassay and by scanning electron microscopy using immunogold labeling techniques. The materials used included vascular graft materials (Dacron and expanded polytetrafluoroethylene) and the National Heart, Lung, and Blood Institute-Devices and Technology Branch reference materials polydimethylsiloxane, polyethylene, and silicone rubber. Factor VIII-von Willebrand factor, another trace plasma protein, and other plasma proteins such as fibrinogen, immunoglobulin G, albumin, fibronectin, and hemoglobin were also detected at the blood-contacting surface. At physiologic flow rates, the adsorption of these proteins from the circulating blood to the surface of these materials appears to be a function of time, with certain materials, as well as of the physical and chemical characteristics of the material surface. Hageman factor adsorption to surfaces, quantified under static conditions, occurs at nanogram concentrations. These data suggest that trace proteins, such as those important in the activation of the coagulation cascade, can significantly affect the blood compatibility or thrombogenicity of an implanted device.

Adsorption↗
PubMed1980

The relative amidolytic activity of Hageman factor (factor XII) and its fragments. The effect of high-molecular-weight kininogen and kaolin.

The effect of HMW kininogen upon the amidolytic properties of two species of activated HF (factor XII), designated HFea and HFf, was studied by using the synthetic substrate S2238. HFea is an agent present in the fluid phase after mixture of HF and Sephadex gels to which ellagic acid has been adsorbed, whereas HFf is the carboxy-terminal fragment separated from HF by limited proteolysis. The specific amidolytic activity of HFea was significantly greater than that of HFf. HMW kininogen enhanced amidolysis by both HFea and HFf. In contrast, kaolin inhibited amidolysis by these enzymes, an effect counteracted by pretreatment of kaolin with HMW kininogen. The mechanisms responsible for these effects of HMW kininogen are uncertain. Its enhancement of amidolysis by fluid-phase HFea ad HFf may be related in part to its capacity to counteract substrate inhibition by S2238. The countervailing effect of HMW kininogen upon the inhibitory properties of kaolin may reflect its capacity to inhibit partially the adsorption of HFea or HFf to kaolin, allowing expression of the amidolytic properties of these enzymes in the fluid phase.

Amides↗
PubMed1987

The genetic relationships between the kringle domains of human plasminogen, prothrombin, tissue plasminogen activator, urokinase, and coagulation factor XII.

A computer-based statistical evaluation of the optimal alignments of the kringle domains of human plasminogen, human prothrombin, human tissue plasminogen activator, human urokinase, and human coagulation Factor XIIa, as well as the putative kringle of human haptoglobin, has been performed. A variety of different alignments has been examined and scores calculated in terms of the number of standard deviations (SD) of a given match from randomness. With the exception of human haptoglobin, it was found that very high alignment scores (8.9-23.0 SD from randomness) were obtained between each of the kringles, with the kringle 1 and kringle 5 regions of human plasminogen displaying the highest similarity, and the S kringle of human prothrombin and the human Factor XII kringle showing the least similarity. The relationships obtained were employed to construct an evolutionary tree for the kringles. The predicted alignments have also allowed nucleotide mutations in these regions to be evaluated more accurately. For those regions for which nucleotide sequences are known, we have employed the maximal alignments from the protein sequences to assess nucleotide sequence similarities. It was found that a range of approximately 40-55% of the nucleotide bases were placed at identical positions in the kringles, with the highest number found in the alignment of the two kringles of human tissue plasminogen activator and the lowest number in the alignment of the S kringle of prothrombin with the second kringle of tissue plasminogen activator. From both protein and nucleotide alignments, we conclude that haptoglobin is not statistically homologous to any other kringle. Secondary structural comparisons of the kringle regions have been predicted by a combination of the Burgess and Chou-Fasman methods. In general, the kringles display a very high number of beta-turns, and very low alpha-helical contents. From analysis of the predicted structures in relationship to the functional properties of these domains, it appears as though many of their functional differences can be related to possible conformational alterations resulting from amino acid substitutions in the kringles.

Amino Acid Sequence↗
PubMed1994

Factor XII fragment and kallikrein generation in plasma during incubation with biomaterials.

Blood biocompatibility of medical devices is in many ways dependent on surface characteristics and biochemical blood material interactions. In this study, the contact system, in which the activation of factor XII and plasma kallikrein is included, is highlighted. This article describes a simple chromogenic assay to determine the Hageman Factor fragment (HFf, or factor XIIf) and kallikrein activity in vitro. The assay is based on conversion of Z-Lys-Phe-Arg-pNA.2HCl to which human factor XIIf and kallikrein appeared to have a high affinity. To discriminate between the serine proteases factor XIIf and kallikrein to cleave this substrate, aprotinin was added to one of two complementary samples. In this in vitro study, standardized disks from glass, high-density polyethylene (HDPE), polytetrafluoro ethylene (PTFE), and polydimethyl siloxane (PDMS) were studied for their capacity to generate factor XIIf and kallikrein in plasma. Kaolin was used as positive control. On glass disks the highest and on HDPE the lowest generation of factor XIIf and kallikrein were found, both with a ratio of 1:1. On PDMS and on PTFE disks protease activities were intermediate, but with a factor XIIf and kallikrein activity ratio of 1:2 and 1:4, respectively. Apparently because of the hydrophobic surface character of PDMS and PTFE, these surfaces absorb or fail to produce the factor XIIf. This assay appeared to be discriminative even for materials that are considered mild activators of the contact system and can therefore be used as a standard method to qualify biomaterials.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1982

Severe Fletcher factor (plasma prekallikrein) deficiency with partial deficiency of Hageman factor (factor XII): report of a case with observation on in vivo and in vitro leukocyte chemotaxis.

A case of cross-reacting material-negative Fletcher trait with additional partial deficiency of Hageman factor (HF, Factor XII) is described. Although the patient presented with a recent history of frequent epistaxis, he had no other personal or family history of a tendency toward bleeding or infection. Similar to other cases of Fletcher trait, his plasma showed a markedly prolonged partial thromboplastin time which could be corrected by prolonged incubation with the surface-activator kaolin. Surface-induced fibrinolysis, amidolysis of alpha-N-benzoyl-proline-L-phenylalanine-L-arginine-p-nitroanilide, and cold-promoted enhancement of factor VII activity, reactions requiring the presence in the plasma of fletcher factor (prekallikrein), in addition to Hageman factor and Fitzgerald factor (high-molecular weight kininogen), were also defective. In vivo chemotaxis of polymorphonuclear leukocytes and monocytes (Rebuck's skin window technique) in response to skin abrasions was defective, but was normal when diphtheria-tetanus toxoid was also applied. In vitro leukocyte chemotaxis (Boyden chamber technique) in response to normal or patient's own serum activated with zymosan was normal. Together with previous observations that kallikrein generated chemotactic activity, possibly via activation of C5, the present observations suggest that prekallikrein activation may be important for in vivo leukocyte chemotactic response to skin abrasion. The inheritance of Fletcher trait in this patient is unclear.l Although the father was an apparent heterozygote, the mother was completely normal for Fletcher factor procoagulant activity and antigen. The mild Hageman factor deficiency in the patient did not contribute significantly to the plasma defects described and was likely inherited from the father who had a low HF procoagulant activity.

Blood Coagulation↗
PubMed1984

Factor XII and prekallikrein-kallikrein-kinin in the cryoactivation of human plasma prorenin.

Cryoactivation of human plasma 'prorenin' was followed for 24 h at -4 degrees C. Chromogenic assays were used to determine factor XII (FXII), FXIIa, prekallikrein and kallikrein in relation to the observed cold-induced increase in plasma renin activity (PRA). Bradykinin activity was also determined using the rat uterus bioassay. PRA increased rapidly and became significantly higher after just 6 h of cryoactivation, by which time prekallikrein had almost disappeared, while kallikrein and kinin levels increased. In contrast, FXII did not change notably, but some FXIIa was indeed formed. The bacteriostat neomycin sulphate did not affect the course of cryoactivation, but did block the dextran sulphate- and kaolin-induced activation of prekallikrein and FXII respectively, and was therefore omitted. Thus cryoactivation of prorenin is accompanied by, and may depend upon, the activation of FXII and prekallikrein, supporting other evidence in favour of this hypothesis.

Adult↗
PubMed2002

Prekallikrein deficiency: the characteristic normalization of the severely prolonged aPTT following increased preincubation time is due to autoactivation of factor XII.

Hereditary plasma prekallikrein (PK) deficiency was diagnosed in a 71-year-old man with an 8-year history of osteomyelofibrosis. PK deficiency was suspected in view of a severely prolonged activated partial thromboplastin time (aPTT) that nearly normalized following prolonged preincubation (10 min) of patient plasma with kaolin-inosithin reagent. Hereditary PK deficiency was demonstrated by very low PK values in the propositus (PK clotting activity 5%, PK amidolytic activity 5%, PK antigen 2% of normal plasma, respectively) and half normal PK values in his children. Normalization of a severely increased aPTT (>120 s) after prolonged preincubation with aPTT reagent occurred in plasma deficient in PK but not in plasma deficient in factor XII (FXII), high-molecular-weight kininogen (HK), factor XI (FXI), factor IX, factor VIII, Passovoy trait plasma or plasma containing lupus anticoagulant. Autoactivation of FXII in PK-deficient plasma in the presence of kaolin paralleled the normalization of aPTT. Addition of OT-2, a monoclonal antibody inhibiting activated FXII, prevented the normalization of aPTT. We conclude that the normalization of a severely prolonged aPTT upon increased preincubation time (PIT), characteristic of PK deficiency, is due to FXII autoactivation.

Aged↗
PubMed2000

Factor XII deficiency in women with recurrent miscarriage.

Congenital thrombophilia is known to cause significant maternal complications, and possibly has an adverse effect on normal fetal development. The aim of this study was to assess the prevalence of factor XII (FXII) deficiency in women with a history of recurrent miscarriage. Two hundred and forty-one consecutive Japanese women with a history of two or more recurrent miscarriages were prospectively assessed for their etiology by conventional screening methods. Seven women were found to have reduced FXII activity (19. 2-46.1%) and prolonged activated partial thromboplastin time (33. 3-51.3 s). Of these 7 women, 6 had experienced early pregnancy losses, while 1 woman had experienced repeated mid-trimester fetal losses with coincidental gestational thrombocytopenia. In 241 women with a history of recurrent miscarriage, the prevalence of FXII deficiency was 2.9%.

Abortion, Spontaneous↗
PubMed1985

The influence of estrogen and prolactin on Hageman factor (factor XII) titer in ovariectomized and hypophysectomized rats.

The synthesis of prothrombin in hepatic microsomes is augmented in intact estrogen-treated rats and in hypophysectomized rats treated with purified prolactin. We investigated the influence of these gonadal and pituitary hormones on the titer of Hageman factor (factor XII), reportedly elevated in women using oral contraceptives. Rats were ovariectomized to minimize the influence of endogenous estrogen and progesterone on the Hageman factor titer. The administration of progesterone did not alter the plasma concentration of Hageman factor. In contrast, the infusion of 17 beta-estradiol induced a marked elevation of the plasma Hageman factor titer, as measured functionally and immunologically. The titer of Hageman factor was directly related to both plasma estradiol and prolactin concentrations, indicating that prolactin may play a role in the regulation of plasma Hageman factor titers. In agreement with this, hypophysectomy induced a marked decrease in the Hageman factor level. In hypophysectomized ovariectomized animals, the administration of estradiol restored the Hageman factor titer to normal levels, whereas the infusion of prolactin induced a dramatic rise in the Hageman factor titer to the degree observed in nonhypophysectomized estrogen-treated rats. No further increase in the Hageman factor titer was observed in rats treated with both estradiol and prolactin. These data indicate that estrogens increase the plasma Hageman factor titer both directly and through its release of prolactin and that prolactin may also increase the titer of Hageman factor through estrogen-independent mechanisms.

Animals↗
PubMed1985

Myocardial infarction with normal coronary arteries and factor XII deficiency.

A 17 year old girl had a myocardial infarction. Three days later coronary angiography showed an occlusive thrombus in the circumflex and anterior descending arteries. The coronary arteries themselves appeared to be normal, and this was confirmed at repeat angiography three months later. Tests of haemostasis showed a deficiency of factor XII.

Adolescent↗
PubMedDate not supplied

[Hemophilia B (factor IX deficiency) with concomitant factor XII degradation in a male crossbreed cat].

A male cat suffered from a severe haemorrhagic disorder manifesting as deep, partly infected cutaneous haematomas, enhanced and prolonged bleeding after injuries and subsequent lameness at several occasions. Bleeding resulted in severe anaemia with haematocrit falling to as low as 0.10 L/L. Haemophilia B was diagnosed based on factor IX deficiency with a functional residual activity of 5% and factor IX antigen of 8%, respectively. Additionally, factor XII activity was reduced to 32% of normal. The mutation 31217G==>A in exon 8 of the factor IX gene, predicting the amino acid exchange G366R was identified as the cause of moderate factor IX deficiency. This is the first mutation identified in cats with haemophilia B. Treatment was limited to local therapy and palliation, insufficient to prevent lethal outcome due to severe anaemia.

Animals↗
PubMed1992

Inhibition of the activation of Hageman factor (factor XII) by aprotinin (Trasylol)

Aprotinin (Trasylol; Bayer AG, Leverkusen, Germany), a protease inhibitor resembling or identical with Kunitz' pancreatic trypsin inhibitor, is said to have anticoagulant properties, but these are not clearly defined. The present study provides evidence that one action of aprotinin is inhibition of the activation of Hageman factor (factor XII).

Aprotinin↗
PubMed1999

Acquired inhibitors to the coagulation factor XII associated with liver disease.

Three patients with liver disease and prolonged activated partial thromboplastine time (APTT) on routine tests are presented. One woman had metastatic liver disease from gastric carcinoma, a second woman had autoimmune hepatitis, and one man had severe chronic hepatitis B. APTT was not corrected after mixing experiments with 25%, 50%, and 75% of normal pool plasma, indicating the presence of an acquired inhibitor. In all three cases, factor XII coagulant activity was reduced: <1%, <1%, and 3%, respectively, while all of the other coagulation factors were normal. In all three cases no other auto-antibody was detected. In the first patient, APTT was normalized after a left liver lobectomy, whereas the primary lesion remained unresected. In the second patient, the FXII activity was improved after corticosteroid therapy but never returned to normal values. In the third patient, the APTT was improved after hydroxychloroquine therapy. None of the patients had hemorrhagic or thrombotic phenomena.

Adult↗