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A case of tonsillectomy in a 22-year-old female patient suffering from isolated deficiency of factor XII is presented. The importance of close cooperation of surgeon and haemostaseologist is pointed out. Preoperative, intraoperative and postoperative precautions are discussed.
The case of an 18-year-old girl with a moderately severe Hageman factor deficiency (Factor XII 2.5%) is described. In this girl, an osteotomy of the pelvis after Chiari was carried out. Both the operation itself and the postoperative healing process were without complications and no signs of any abnormal tendency to haemorrhage were observed. Blood transfusions were not necessary. On the basis of this observation and a review of the literature for the attempt is made to establish general guide lines the procedure to be adopted for surgery in cases of Hageman factor deficiency.
Hereditary and acquired C1-inhibitor (C1-INH) deficiencies (hereditary angioedema, HAE and acquired angioedema, AAE) are characterized by episodic increases in vasopermeability due to kinin release. Despite continuously defective C1-INH levels, symptoms only recur occasionally suggesting an episodic generation of pathogenetic factors induced by activation of the protease systems regulated by C1-INH. We evaluated activation of factor XII by measuring plasma levels of FXIIa with a commercial ELISA and cleavage of high molecular weight kininogen by performing SDS PAGE and immunoblotting analysis during 5 attacks in 5 different patients with HAE and during 7 attacks in 3 patients with AAE. The patients were also studied during remission. We confirmed our previous data indicating that during attacks both HAE and AAE patients had very high levels of cleaved HK (p < 0.0001) whereas during remission cleaved HK levels were normal in HAE and significantly increased in AAE (p < 0.0001). Both in HAE and in AAE, plasma levels of FXIIa were normal during remission and significantly increased during acute attacks (p = 0.0126; p = 0.0003). Our data suggest that the activation of a contact system is required to produce clinical symptoms.
It is well known that activated Factor XII (FXIIa) and kallikrein are rapidly inactivated in plasma as a result of reaction with endogenous inhibitors. The purpose of this may be to prevent uncontrolled deleterious spreading and activation of target zymogens. Both FXII and the complex plasma prekallikrein/high molecular mass kininogen become activated when they bind, in a Zn2+-dependent manner, to receptors on human umbilical vein endothelial cells (HUVEC). The C1-esterase inhibitor (C1-INH) is by far the most efficient inhibitor of FXIIa. In the present study it has been investigated whether binding of FXIIa to HUVEC might offer protection against inactivation by C1-INH. It appeared that the relative amidolytic activity of purified FXIIa bound to the surface of HUVEC decreased according to the concentration of C1-INH in medium; however, the decrease was smaller than that measured for inactivation of FXIIa in solution. The secondary rate constant for the inactivation was 3-10-fold lower for cell-bound than for soluble FXIIa. The inactivation was found to be caused by C1-INH binding to cell-bound FXIIa. Accordingly, the amidolytic activity of saturated amounts of cell-bound FXIIa was reduced in the presence of C1-INH and was theoretically nonexistent at physiological C1-INH concentrations. Amidolytic activity was, however, present on HUVEC incubated with plasma indicating that the endogenous C1-INH did not completely abolish the activity of FXIIa generated during the incubation period. This supports the hypothesis that binding to endothelial cells protects the activated FXII against inactivation by its major endogenous inhibitor. Hence, the function of FXII may be localized at cellular surfaces.
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The mechanism by which negatively charged substances such as celite, kaolin, or ellagic acid contribute to the surface-dependent activation of Hageman factor (Factor XII) was studied. Kinetic studies of the proteolytic activation of (125)I-labeled human Hageman factor by human plasma kallikrein, plasma, activated Factor XI, and trypsin were performed in the presence and absence of high molecular weight kininogen and surface materials such as celite, kaolin, or ellagic acid. The results showed that surface-bound Hageman factor was 500 times more susceptible than soluble Hageman factor to proteolytic activation by kallikrein in the presence of high molecular weight kininogen. Surface binding of Hageman factor enhanced its cleavage by plasmin, activated Factor XI, and trypsin by 100-fold, 30-fold, and 5-fold, respectively. On a molar basis, trypsin was twice as potent as kallikrein in the cleavage of the surface-bound Hageman factor, while plasmin and activated Factor XI were an order of magnitude less potent than kallikrein. Kallikrein even at concentrations as low as 0.5 nM (i.e., 1/1000th of the concentration of prekallikrein in plasma) was very potent in the limited proteolysis of the surface-bound Hageman factor. These results suggest that substances classically known as "activating surfaces" promote the activation of Hageman factor indirectly by altering its structure such that it is much more susceptible to proteolytic activation by other plasma or cellular proteases.
INTRODUCTION: The contact system proteins factor XII (FXII), prekallikrein (PK) and high molecular weight kininogen (HK) have roles in coagulation, fibrinolysis, thrombin-induced platelet activation, cell adhesion and angeogenisis. It has been suggested that inherited or acquired deficiencies of these proteins may be risk factors for thrombosis. Studies on the levels of FXII in plasma from normal and thrombotic patient populations have been reported, to our knowledge however, no systematic study on plasma levels of PK and HK in large populations of normal blood donors and patients having had venous thrombotic events has been performed. MATERIALS AND METHODS: Chromogenic substrate assays were used to measure plasma levels of FXII, PK and HK in 300 normal blood donors (ND) and 300 patients attending our anticoagulant clinic who had a history of venous thrombosis (deep vein thrombosis or pulmonary embolism [VT]). All subjects were Caucasian, antiphospholipid antibody negative and had normal liver function. RESULTS: Mean values +/- SD were: FXII: ND 99.4 +/- 26.7%: VT 91.0 +/- 27.2%: PKK: ND 99.7 +/- 19.8%: VT 99.1 +/- 21.2%: HK: ND 101.0 +/- 20.5%: VT 110.7 +/- 32.3%. Statistical analysis of the data revealed significantly lower (p< or =0.001) mean values for FXII and significantly higher (p< or =0.001) mean values for HK in the VT group. Calculated lower limits of normal for each parameter were: FXII: 49.1%, PKK: 66.8%, HK: 63.4%. The prevalence of values below the lower limit of normal were FXII-ND 2.3%: FXII-VT 8.0%, PKK-ND 3.0%: PKK-VT 4.7%, HK-ND 2.3%: HK-VT 5.0%. No homozygous deficiency patients were found for any parameter. One VT patient had combined FXII and HK deficiency and one ND and two VT patients had combined PK and HK deficiency. CONCLUSIONS: FXII levels were lower and HK levels and the prevalence of FXII, PK and HK deficiency higher in a population of patients with a history of VT than in a population of healthy blood donors.
A dot immunobinding assay on nitrocellulose (NC) membranes has been developed for the quantification of human coagulation factor XII (F XII). Plasma samples were dotted on to NC filters and F XII was detected using a polyclonal antiserum followed by a radiolabelled antigen overlay. Dilutions of either pooled normal human plasma (NHP) or purified F XII in F XII deficient plasma were used as standards. Quantification was performed by measuring the radioactivity of bound 125I-F XII. Precise measurements of F XII antigen (F XII: Ag) were possible with a sensitivity down to 0.12 ng. Thus, dotting samples containing 0.5 microliter of plasma permitted detection of a F XII concentration corresponding to 1% of the level in NHP. The intra-assay coefficient of variation (CV) was less than 5% and the interassay CV was less than 16%. F XII:Ag in plasma samples of 50 healthy adults ranged from 12 micrograms/ml to 47 micrograms/ml. A good correlation (r = 0.93) existed between F XII:Ag and F XII clot promoting activity (F XII:C) in these samples. NHP contained 24.1 micrograms/ml F XII:Ag confirming earlier results obtained by other methods. In 16 pregnant women levels of F XII:Ag as well as of F XII:C were elevated, but F XII:Ag was disproportionately higher compared with F XII:C. The immunobinding assay has the following advantages: (1) rapid quantification of large numbers of samples is possible, (2) the sensitivity down to 1% of NHP is better than that of several other methods, (3) only very small amounts of both test material and reagents are needed.
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It is well known that on artificial surfaces, binding and autoactivation of factor XII (FXII) is the initiating event of plasma prekallikrein (PK) activation. We performed investigations to examine whether this mechanism was true for FXII activation on endothelial cells (HUVEC). Activation of PK on HUVEC required an optimal substrate and Zn2+ concentration, the latter of which varied with the buffer's carrier protein. Maximal PK activation required the addition of 250 microM or 10 microM Zn2+ to buffers containing bovine serum albumin (BSA) or gelatin, respectively. However, the actual free Zn2+ concentration in these buffers was the same at 8 microM. In both BSA- and gelatin-containing buffers and using two different chromogenic substrates for FXII, no autoactivation of FXII on HUVEC was seen when incubated for up to 60 min. Rather, initiation of FXII enzymatic activity required the presence of PK. FXII activation after PK activation contributed to the extent of measured enzymatic activity, but its role was secondary because treatment with corn trypsin inhibitor or a neutralizing antibody to FXIIa did not abolish the measured enzymatic activity. They also reduced the activity to the level seen with PK activation alone. Alternatively, soybean trypsin inhibitor abolished the proteolytic activity associated with PK and FXII activation on HUVEC. Further, only normal human and FXII-deficient plasmas, not PK-deficient plasma, had the ability to generate proteolytic activity when incubated over endothelial cells. In a purified system, maximal PK activation was measured after a 10-15 min incubation depending upon the concentration of reactants. When FXII was added with the PK, maximal activation occurred within 7.5-10 min. In normal human or FXII-deficient plasmas, but not in PK-deficient plasma, maximal activation was seen in 4 min. These data indicate that on HUVEC, unlike artificial surfaces, PK activation when bound to HK is the initiating activation event in this system. FXII activation is secondary to PK activation and contributes to the extent of measured enzymatic activity. These data challenge the accepted dogmas of "contact activation" and suggest that on biologic membranes a new notion as to how this system is activated needs to be considered.
A 12-year-old girl with lifelong hemorrhagic episodes was found to have both a dys-form of homozygous factor XI deficiency and heterozygous factor XII deficiency. The heredity of the coagulation defects was confirmed by family studies. Severe bleeding after dental surgery occurred in spite of replacement therapy and local measures including fibrin glue. Our findings suggest that the risk of bleeding in patients with homozygous factor XI deficiency must not be underestimated and that the most effective measure is the transfusion of sufficient amounts of fresh frozen plasma until at least the 5th postoperative day.
The incubation of normal human plasma in the presence of sulphatide vesicles results in the generation of amidolytic activity due to factor XIIa (FXIIa) and to kallikrein (KRN). The progress of the generation of the enzymes distinguished a high initial rate of enzyme generation, a decline of this rate to maximum amidolytic activity ([FXIIa]m and [KRN]m) and a negative pseudo-first-order rate attributed to enzyme inactivation by plasma C1-inhibitor (C1INH). [FXIIa]m and [KRN]m were determined after the treatment of various dilutions of plasma in the presence of 4, 15, or 40 microM sulphatide vesicles. At all levels of sulphatides, [FXIIa]m and [KRN]m initially increased with the concentration of plasma, to reach a plateau at higher concentration of plasma. The plateau activities of the generated enzymes and the optimal concentration of plasma both increased with the level of sulphatide vesicles. The pseudo-first-order inactivation rate for KRN increased progressively with the concentration of plasma but the respective rate for FXIIa was independent of the plasma concentration. The data suggest that contiguous binding of plasma FXIIa, factor XII (FXII), and the complexes of high molecular weight kininogen (HK) with prekallikrein (HK-PKRN) and factor XI (HK-FXI) to an electronegative surface induces a rapid generation of FXIIa and KRN. The concentration of the electronegative surface controls the levels of generated FXIIa and KRN and their release to the bulk phase. The released FXIIa and KRN are both inactivated by C1INH.
gC1qBP is a novel cell protein which was found to interact with the globular heads of C1q, high mol. wt kininogen, factor XII and the heparin-binding, multimeric form of vitronectin. The protein sequence shows no homology to any protein family. This paper describes the genomic organization of mouse gC1qBP and the characterization of its 5' flanking region. The mouse gene consists of six exons separated by five introns, and its total length is approximately 6kb. Exon 1 encodes the putative signal peptide, a long stretch of 70 amino acid residues, and the first four amino acid residues found in the mature gC1qBP. Exons 2-5 encode four very hydrophilic domains, whereas exon 6 encodes a neutral domain. The amino acid sequence responsible for binding to the heparin-binding, multimeric form of vitronectin is located in exon 2. A 1kb DNA fragment upstream of the first initiation codon was sequenced, which contained four potential TATA boxes, seven CAAT boxes, six SP1 sites and various putative transcription factor-binding elements, indicating that the promoter region is in close proximity to the first exon. The mouseC1qbp gene was mapped to chromosome 11, closely linked to D11Mit4 using genomic DNAs from a (C57BL/6J x Mus spretus)F1 x Mus spretus backcross.
We investigated hemodialysis membrane biocompatibility with respect to contact phase activation by determination of FXII-like activity (FXIIA) on the membrane surface and in the supernatant phase, during plasma contact with various hemodialysis membranes using an in vitro incubation test cell. The results were compared to the influence of these membranes on the activation of purified FXII. A time course for the generation of activated FXII using purified FXII solution at physiologic concentrations on two similar negatively charged polymers was performed. The membranes assessed were regenerated cellulose (Cuprophan; Akzo Faser AG, Germany), modified cellulosic (Hemophan; Akzo Faser AG), acrylonitrile-sodium methallyl copolymer-based membrane AN69S (Hospal, France), and SPAN, a new polyacrylonitrile-based copolymer (akzo Nobel AG). The plasma FXIIA at the membranes surface was significantly different between the membranes, while the supernatant phase FXIIA exhibited no significant differences. In contrast, activation of purified FXII in a plasma-free system with respect to supernatant activity indicated significant differences between the materials. A similar finding for the membrane-bound factor XIIA was also observed when purified factor XII was used. The membrane-bound FXIIA values observed in the plasma system containing heparin were significantly greater than in citrated plasma. This demonstrated the strong influence of heparin and the interaction of other plasma components to the membrane surface on the activation of contact phase of coagulation.
The supernatant fluid (conditioned medium) of cultured human vascular endothelial cells inhibits activation of Hageman factor (factor XII), whether by ellagic acid, bovine brain sulfatides, or bismuth subgallate; inhibition appears to be a property of one or more proteins in the culture supernates. This phenomenon may contribute to maintaining the fluidity of circulating blood by inhibiting surface activation of the intrinsic pathway of coagulation.
In this paper are described the immunological and molecular procedures that have allowed the identification and the nucleotide sequence characterization of recombinant cDNA coding for factor XII of human coagulation and have suggested the possible identification of other cDNA clones as coding for factor VII of human coagulation.
A protein derived from sweet corn or popcorn inhibits the enzymatic activity of the carboxy-terminal fragment of Hageman factor (HFf) and of ellagic acid-activated Hageman factor (HF, factor XII). Not clarified is whether the inhibitor is directed at the active site of HF. Filtration of normal plasma or purified HF through columns of popcorn inhibitor bound to agarose gels demonstrated that HF was bound to these gels and could then be eluted by buffers containing 2.0 mol/L sodium chloride. The eluted HF was in the precursor form. Thus, popcorn inhibitor appeared to attach to a point on the carboxy-terminal HFf that was distinct from the enzymatically active site of this clotting factor.