HAGEMAN FACTOR DEFICIENCY IN A CHILD.
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Adolescent↗
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Purification and characterization of a plasma factor which cleaves single-chain form of t-PA and u-PA.
Low molecular weight heparin (LMW-heparin) enhanced the amidolytic activity of plasma when the chromogenic substrate, H-D-Ile-Pro-Arg-pNA (S-2288), was used. The amidolytic activity increased in a time-dependent manner as the LMW-heparin concentration increased and reached its peak at around 15 mu/ml. Factor XII-deficient plasma increased the S-2288 amidolytic activity by LMW-heparin. In order to clarify the mechanism of the heparin-induced enhancement of the amidolytic activity, a plasma factor was purified. The plasma factor was obtained from human normal plasma by ammonium sulfate fractionation, followed by successive column chromatography with heparin-Sepharose, zinc chelate-Sepharose, aprotinin-Sepharose and protein A-Sepharose. The plasma factor so purified revealed a major band (88% of total protein) at 80 kD with several minor bands on analysis by SDS-PAGE. The plasma factor exhibited an intrinsic amidolytic activity, which was enhanced by heparin. The plasma factor further enhanced the amidolytic activity of sct-PA and scu-PA, the enhancement of which was of much greater degree than that for LMW-heparin. However, when the two-chain form of t-PA or u-PA was reacted with the plasma factor and LMW-heparin, no enhancement of the amidolytic activity of these enzymes was observed. The plasma factor cleaved a peptide bond of sct-PA and scu-PA and induced a structural change from a single-chain to a two-chain form. The amidolytic activity of the plasma factor was not inhibited by anti-t-PA IgG, anti-u-PA IgG, anti-plasminogen IgG, anti-factor XII IgG or anti-plasma prekallikrein IgG. These findings suggest an important role for the plasma factor in the activation of sct-PA and scu-PA in heparin-dependent fibrinolysis.
Amides↗
[Contact factors (factor XII and XI)--how to read its figures].
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Disseminated Intravascular Coagulation↗
Intracoronary thrombolysis in the treatment of graft closure immediately after CABG.
A patient with a hypercoagulable state underwent coronary artery bypass grafting and was recovering uneventfully until diffuse electrocardiographic changes and cardiogenic shock developed within hours of the operation. Because of severe hemodynamic compromise on high-dose inotropic drugs and intraaortic balloon pump support, she was taken to the catheterization laboratory, where the patient was discovered to have thrombotic occlusion of all grafts, including the left internal mammary artery to the left anterior descending artery. Multiple graft percutaneous transluminal coronary angioplasty and thrombolysis with urokinase successfully opened the grafts, without bleeding complication. Anastomoses were all free of significant anatomic lesion. She has remained free of cardiac symptoms for 3.5 years after operation.
Angioplasty, Balloon, Coronary↗
Cleavage of human high-molecular weight kininogen by purified kallikreins and upon contact activation of plasma.
To study the digestion pattern of human high-molecular weight (mol wt) kininogen (HMWK) in plasma during contact activation we have prepared monoclonal antibodies (MoAbs) to the light-chain (LC) and the heavy-chain moiety of HMWK. One MoAb from each set was purified, and neither MoAb inhibited the clotting activity of HMWK. In enzyme-linked immunosorbent assay and immunoblotting experiments neither antibody bound to kininogen-deficient plasma. Digestion of purified HMWK with plasma kallikrein yielded, on reduced sodium dodecyl sulfate gels, two LC forms, at 62 and 49 kd, respectively. Digestion of HMWK with tissue kallikrein (TK) yielded mainly the 62-kd form. In immunoblot analyses of these digests, the anti-LC MoAb detected products at 62 and 49 kd respectively. With plasma kallikrein, the 62-kd species slowly shifted to 49 kd, and with TK, the 62-kd species accumulated with time. Anti-LC MoAb was also used as a probe in immunoblotting experiments to study the digestion pattern of HMWK in whole plasma activated with kaolin or dextran sulfate. In activated normal pooled plasma (NHP) and factor XI-deficient plasma, native HMWK (mol wt, 115 kd) was cleaved within five to ten minutes, and two LC forms at 62 and 49 kd were detected. In kaolin-activated prekallikrein (PK)-deficient plasma, the disappearance of the 115-kd form was relatively slow, and only the 62-kd form of LC was seen. HMWK was not cleaved when factor XII-deficient plasma was incubated with kaolin. LC-dependent coagulant activity paralleled the presence of LC bands seen in the immunoblots, and lower-mol wt fragments of LC were not identified. These data indicate that in activated NHP two forms of LC of HMWK (62 and 49 kd) are formed sequentially. Further, the LC-dependent coagulant activity remains detectable long enough to suggest that proteolytic inactivation of LC is too slow to be an important control mechanism.
Antibodies, Monoclonal↗
A new assay for the determination of factor XII in plasma using a chromogenic substrate and a selective inhibitor of plasma kallikrein.
A new chromogenic assay for factor XII in plasma was designed by the use of the soluble activator Kalliplastin, the substrate H-D-HHT-Gly-Arg-pNA and a synthetic inhibitor of plasma kallikrein (Pefabloc PK). The assay was carried out in one and the same cuvette and did not require factor XII-deficient plasma. There was a good correlation between F XII coagulant and amidolytic assays.
Benzamidines↗
The hypercoagulable states.
Patients are considered to have hypercoagulable states if they have laboratory abnormalities or clinical conditions that are associated with an increased risk of thrombosis (prethrombotic states) or if they have recurrent thrombosis without recognizable predisposing factors (thrombosis-prone). The number of specific primary hypercoagulable states that are recognized is growing. These disorders are generally inherited abnormalities of coagulation in which a physiologic anticoagulant mechanism is defective: for example, antithrombin III deficiency, protein C and protein S deficiency, abnormalities of the fibrinolytic system, and dysfibrinogenemias. Secondary hypercoagulable states are generally acquired disorders in patients with underlying systemic diseases or clinical conditions known to be associated with an increased risk of thrombosis: for example, malignancy, pregnancy, use of oral contraceptives, myeloproliferative disorders, hyperlipidemia, diabetes mellitus, and abnormalities of blood vessels and rheology. The complex pathophysiologic features of these secondary hypercoagulable states are discussed, and a framework is provided for the laboratory investigation and systematic clinical approach to the patient.
Antithrombin III Deficiency↗
The interaction of Hageman factor and immune complexes.
The possible interaction of Hageman factor from human or rabbit plasma with a variety of immunologic reactants was studied. Evidence of an interaction was not obtained and neither binding of radiolabeled Hageman factor to immune aggregates nor depletion of the Hageman factor from the supernate was observed. Cleavage of the labeled Hageman factor molecule into its 30,000 molecular weight-active fragments was not detectable after incubation with immune complexes. Isolated Hageman factor was far more sensitive to activation than Hageman factor in plasma or serum. There was no consistent activation of isolated Hageman factor by immunologic reactants as determined by conversion of prekallikrein to its enzymatic form or by shortening of the clotting time of factor XII-deficient plasma. A variety of immunologic stimuli were tested: (a) antigen-antibody complexes in soluble or precipitated form; (b) particulate antigen-antibody complexes, i.e., zymosan-anti-zymosan in which a surface was presented for activation; (c) human IgM-IgG and IgG-IgG (rheumatoid factor) complexes; (d) immune aggregates consisting of heat or bis-diazotized benzidine-aggregated myeloma proteins of all human immunoglobulin classes and subclasses: IgG(1,2,3,4), IgA, IgD, IgM, and IgE. Absorption with immune aggregates did not reduce the quantity of Hageman factor in solution, nor was the Hageman factor bound to the precipitates. The presence of plasma or serum with immune aggregates did not generate activity of the Hageman factor. The only preparations of immunoglobulins capable of activating Hageman factor were found to be contaminated with bacteria. These bacteria, upon isolation, activated Hageman factor.
Animals↗
Spontaneous fibrinolysis in whole human plasma. Identification of tissue activator-related protein as the major plasminogen activator causing spontaneous activity in vitro.
Spontaneous fibrinolysis of plasma clots was studied by following the lysis of the clots formed in 125I-fibrinogen-supplemented citrated plasma. Lysis of the clots invariably follows sigmoidal kinetics with S50 (the time required for 50% clot lysis) ranging from 3.5 to 4.7 days in 8 samples of pooled blood bank plasma and in the majority of apparently healthy donor plasmas. The spontaneous lysis of factor XII-deficient and prekallikrein-deficient plasmas was found to be similar to that of normal plasma. Addition of ellagic acid or antibodies against kallikrein or urokinase to normal pooled plasma did not alter significantly its rate of spontaneous lysis. On the other hand the addition of antibody against tissue activator (t-PA) inhibited over 80% of the spontaneous fibrinolysis in a 7-day incubation period at 37 degrees C, and the clot visually persisted for more than a month. Therefore, the factor XII-dependent components and prourokinase/urokinase system do not contribute significantly in whole plasma fibrinolysis in vitro, while the t-PA-related protein appears to be the major plasminogen activator responsible for initiating spontaneous fibrinolysis in whole plasma. Exogenous addition of increasing amounts of purified HeLa cell t-PA to normal pooled plasma in the ng/ml range cause progressively faster clot lysis. By extrapolation, normal pooled plasma is found to contain endogenous tissue activator in an amount functionally equivalent to 2 ng/ml of purified 60-kDa t-PA. The molecular nature of the t-PA-related proteins in plasma was studied by zymographic and immunological methods. The major t-PA-related protein in plasma was found to have a molecular mass of 100 kDa as determined by zymography. By incubating purified HeLa 60-kDa t-PA with a t-PA-depleted plasma, the 100-kDa component can be generated in plasma, suggesting that the latter is formed as a result of the binding of 60-kDa t-PA to a binding protein in plasma.
Antibodies↗
Screening for inherited thrombotic disorders.
In order to determine a scheme for the screening of inherited thrombotic disorders, abnormalities considered as predisposing to thrombosis have been reviewed. Owing to the low prevalence of biological alterations, a selection of patients is required: documented venous thromboses, possibly at unusual sites (mesenteric vein, portal, cerebral veins), occurring before the age of 40 in patients with a positive family history of thromboses are relatively frequently associated with coagulation abnormalities. In addition, patients with skin necrosis at the initiation of oral anticoagulants, or with repeated superficial vein thrombosis or unexplained arterial occlusions at a young age might be included for screening. Tests have also to be selected. Some abnormalities, such as congenital deficiencies in antithrombin III, protein C and protein S, are recognized risk factors and have to be searched. Some others cannot be at present considered as definite risk factors (e.g., dysfibrinogenemias or deficiencies in factor XII), but their detection is easy by routine tests: prothrombin time, fibrinogen assay. Other abnormalities are recognized risk factors (or not) and need specific uncommon tests (e.g., study of fibrinolysis). Each time a biological abnormality is found, it is important to verify it is isolated since combined deficiencies have been observed and we should be able to answer the question whether the abnormality is the cause or the consequence of thrombosis, or a coincidence. Finally, in our experience, even in well selected patients, a coagulation disorder is detected in less than 30% of patients, so that new tests are needed to improve our knowledge in this field.
Antithrombin III Deficiency↗
Alteration of factor VII activity by activated Fletcher factor (a plasma kallikrein): a potential link between the intrinsic and extrinsic blood-clotting systems.
Although surface contact is known to accelerate the one-stage prothrombin time of human plasma through the participation of Hageman factor (factor XII) and factor VII, it has not been clear whether Hageman factor interacts with factor VII directly or indirectly. Recently, Gjønnaess reported experiments suggesting that plasma kallikrein was an intermediate between Hageman factor and factor VII. The present study was undertaken to elucidate the interaction of plasma kallikrein and factor VII. Incubation of Fletcher-trait plasma (deficient in a plasma prekallikrein) with kaolin at 0 degrees C. did not induce shortening of the Thrombotest time or enhancement of factor VII activity, in contrast to studies of normal plasma. Monospecific rabbit antiserum against plasma kallikrein blocked the shortening of the Thrombotest time of normal plasma brought about by kaolin. Purified Hageman factor fragments (prekallikrein activator) induced an increase in factor VII activity in normal or Hageman-trait plasma, but not in Fletcher-trait plasma. A purified plasma kallikrein preparation enhanced factor VII activity in all plasmas, including that of Fletcher-trait plasma. The effect of the kallikrein preparation was blocked by soybean trypsin inhibitor, Trasylol, or rabbit antiserum against kallikrein, but not by lima bean trypsin inhibitor or antiserum against Hageman factor. The activity of partially purified factor VII was enhanced by purified kallikrein in the presence, but not in the absence of factor VII-deficient plasma. These results further support the idea that the enhancement of factor VII activity by surface contact is via Hageman factor and plasma kallikrein, suggesting a possible link between the intrinsic and extrinsic pathway of blood clotting. The significance of this phenomenon in hemostasis in vivo remains to be elucidated.
Animals↗
[Determination of factor XII in blood products and correction of its deficiency after plasma transfusion in a case].
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Adolescent↗
Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency.
PURPOSE: We tested the hypothesis that Sotos syndrome (SoS) due to the common deletion is a contiguous gene syndrome incorporating plasma coagulation factor twelve (FXII) deficiency. The relationship between FXII activity and the genotype at a functional polymorphism of the FXII gene was investigated. METHODS: A total of 21 patients including those with the common deletion, smaller deletions, and point mutations, and four control individuals were analyzed. We examined FXII activity in patients and controls, and analyzed their FXII 46C/T genotype using direct DNA sequencing. RESULTS: Among 10 common deletion patients, seven patients had lower FXII activity with the 46T allele of the FXII gene, whereas three patients had normal FXII activity with the 46C allele. Two patients with smaller deletions, whose FXII gene is not deleted had low FXII activity, but one patient with a smaller deletion had normal FXII. Four point mutation patients and controls all had FXII activities within the normal range. CONCLUSION: FXII activity in SoS patients with the common deletion is predominantly determined by the functional polymorphism of the remaining hemizygous FXII allele. Thus, Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency.
Adolescent↗
Advances and dilemmas in factor XI.
Factor XI is a key component of the intrinsic pathway of blood coagulation in vitro. The poor correlation between the clinical bleeding diathesis in factor XI deficiency and abnormalities in clotting assays that measure intrinsic coagulation brings into question the role of this serine protease in in vivo hemostasis. The characterizations of the point mutations responsible for the majority of cases of severe factor XI deficiency in Ashkenazi Jews and subsequent epidemiologic studies have provided insight into the perplexing hemostatic abnormalities in this disorder. It appears that excessive bleeding in factor XI deficiency depends on the severity of the deficiency in certain situations and on the location of the hemostatic challenge in others. Additional coexisting abnormalities of hemostasis, such as von Willebrand's disease, may also be responsible for variation in clinical presentation, particularly in those individuals with mild factor XI deficiency. The absence of abnormal bleeding in congenital deficiency of factor XII, the protease that activates factor XI in the intrinsic cascade, has stimulated a search for other mechanisms for factor XI activation. Recent studies have pointed to the serine protease thrombin and autoactivation by activated factor XI as possible alternatives to factor XII as activators of factor XI. These findings suggest that factor XI, rather than operating in a pathway for the initiation of hemostasis, may function in the consolidation of clot formation after the initiation of the hemostatic process by other mechanisms.
Amino Acid Sequence↗
Relation between renin and prorenin in plasma from hypertensive patients and normal people: evidence for different renin:prorenin ratios.
Renin and prorenin concentrations in plasma correlate closely, but the proportion of active renin to prorenin shows some variation in different forms of hypertension. The proportion of active renin to prorenin is higher in normal renin essential hypertensives and in patients with renal hypertension than in normal subjects, and it is lower in low renin essential hypertension and primary hyperaldosteronism. Plasma deficient in plasma prekallikrein shows a lower proportion of active renin than might be expected. Active renin and plasma angiotensin II concentration show a strong correlation while prorenin correlates weakly with plasma angiotensin II concentration.
Angiotensin II↗
Demonstration and mode of action of an inhibitor for activated Hageman factor (factor XIIa) of the intrinsic blood coagulation pathway from Schistosoma mansoni.
An anticoagulant activity from adult Schistosoma mansoni whole worm homogenate is described. The inhibitor appears to be specific for the contact activation step of the intrinsic pathway. Experiments with both human and mouse plasmas have defined the specificity of the inhibitor as follows: (1) It lengthens the partial thromboplastin time of normal plasma. (2) It has no effect on the prothombin time and Russell's viper venom time of normal plasma. (3) Preactivation of normal plasma by a contact activator such as Celite eliminates essentially all inhibitory activity. (4) The inhibitor appears to be heat stable and can be precipitated by centrifugation above 27,000 g. (5) The inhibitor has no effect on the activation of factor XII by Celite. (6) The activation of factor XI by factor XIIa, however, is inhibited by the schistosomal inhibitor. The above data are consistent with the view that S. mansoni adults possess an anticoagulant that is capable of specifically inhibiting the conversion of factor XI to factor XIa by factor XIIa.
Animals↗
Thrombin-mediated activation of endogenous factor XI in plasma in the presence of physiological glycosaminoglycans occurs only with high concentrations of thrombin.
The variable bleeding tendency associated with a genetic deficiency of factor XI (FXI) and the lack of bleeding disorders in individuals with a genetic deficiency of factor XII (FXII) suggest an alternative mechanism for FXI activation in vivo. Recently, thrombin has been shown to activate FXI. However, in plasma this activation has been shown to occur only with exogenous FXI and a non-physiological cofactor (sulphatides), and the occurrence of this reaction in a plasma environment has been questioned. Using recently developed sensitive assays for FXIa-inhibitor complexes we found thrombin-mediated and FXII-dependent activation of endogenous FXI in plasma in the presence of heparan sulphate, heparin, dermatan sulphate or dextran sulphate. Using heparan sulphate, which is present in the human vascular system, activation of about 1-2% of plasma FXI was observed, however, only after addition of very high amounts (500 nmol/l) of human alpha-thrombin to FXII-deficient plasma (at a 1 to 4 final dilution). We conclude that endogenous FXI in plasma can be activated by thrombin in the presence of various glycosaminoglycans, including the physiological compounds heparan sulphate and dermatan sulphate, but only at very high concentrations of thrombin, corresponding to 100% prothrombin activation in undiluted plasma.
Blood Coagulation↗