[Hageman factor. Present-day views].
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Factor XI↗
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Results for “Factor XI Deficiency”
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Identifying hypocoagulable states with a modified global assay of overall haemostasis potential in plasma.
To test the sensitivity of the global assay of overall haemostasis potential (OHP) in detecting hypocoagulation, the OHP was assayed in plasma containing exogenous thrombin (0.04 IU/ml), tissue-plasminogen activator (330 ng/ml), Ca and a platelet reagent. Commercial plasmas with factor II, V, VIII, IX, X, XI, XII or VII deficiency were mixed with normal plasma in different proportions to imitate different severities. Samples from patients with haemophilia and factor XII deficiency were also examined. No clot was found in the absence of factor II/factor X, indicating that the tiny dose of thrombin worked solely as a trigger for the intrinsic pathway activation. Changed levels of the investigated coagulants, apart from factor XII, influenced the outcome. OHPs were decreased in patients with haemophilia but were unchanged or even increased in those with factor XII deficiency. This modified OHP method may therefore be useful for estimating the bleeding tendency in haemophilic patients and to find suitable doses and intervals for prophylactic treatment. It may also be of use in investigations of the effect of antifibrinolytic drugs as well as for identifying a thrombotic tendency in patients with factor XII deficiency. For detection of other coagulation factor deficiencies, our investigations with the commercial plasmas suggest that the OHP assay is also valuable, especially when the intrinsic pathway of the coagulation cascade is impaired.
Blood Coagulation↗
Naturally occurring human antibodies against two distinct functional domains in the heavy chain of FXI/FXIa.
We have isolated and probed the mechanism of action of two naturally occurring antibodies (Baltimore and Winston-Salem) against factor XI (FXI), that developed in patients congenitally deficient in FXI after replacement therapy. Purification on immobilized protein A and neutralization with monospecific antibodies against IgG heavy and light chain subtypes indicated that both antibodies were of restricted heterogeneity. Both Winston-Salem (IgG3 kappa) and Baltimore (IgG1 kappa) completely inhibited FXI coagulant activity at titers of 200 and 8 Bethesda units, respectively. Immunoaffinity columns prepared from each antibody were able to bind the heavy but not the light chain of reduced and alkylated activated FXI (FXIa). The activation of purified FXI by activated bovine factor XII (FXIIa), a reaction independent of high molecular weight kininogen (HK), was not inhibited by either antibody. The active site on the FXIa light chain was unaffected by either patient's IgG, as measured by its amidolytic activity. In contrast, one antibody (Baltimore) or its Fab' blocked the surface-mediated proteolytic activation of FXI by human FXIIa in a concentration-dependent fashion by preventing its binding to HK, but had no effect on the rate of activation of FIX by FXIa. In contrast, the other antibody (Winston-Salem) or its Fab' inhibited the activation of FIX by FXIa in a concentration-dependent fashion but did not inhibit binding of FXI to HK. We conclude that each of these two naturally occurring antibodies is directed against a specific, separate, and distinct epitope located in the heavy chain of FXIa, one near or at the domain essential for the activation of FIX by FXIa and the other close to the domain required for binding to HK.
Amides↗
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↗
Hageman factor substrates. Human plasma prekallikrein: mechanism of activation by Hageman factor and participation in hageman factor-dependent fibrinolysis.
Two molecular forms of prekallikrein can be isolated from pooled normal human plasma. Their approximate molecular weights by sodium dodecyl sulfate-gel electrophoresis are 88,000 and 85,000. The two bands observed are shown to represent prekallikrein by functional, immunochemical, and structural criteria. Both forms are cleaved by activated Hageman factor, they appear to share antigenic determinants, they are not interconvertible upon incubation with activated Hageman factor or kallikrein, and the ratio of kinin-generating, and plasminogen-activating activities of the preparations are independent of the relative proportion of each band. Activated Factor XII converts prekallikrein to kallikrein by limited proteolysis and two disulfide-linked chains designated kallikrein heavy chain (Mr = 52,000) and kallikrein light chains (Mr = 36,000 or 33,000) are formed. The active site is associated with the light chains as assessed by incorporation of [3H]diisopropyl fluorophosphate. No dissociable fragments were observed in the absence of reducing agents. However, kallikrein could digest prekallikrein to diminish its molecular weight by 10,000. In addition, two factors capable of activating plasminogen to plasmin have been isolated; one is identified as kallikrein. The second principle fractionates with Factor XI and is demonstrable in normal and prekallikrein-deficient plasma.
Enzyme Activation↗
The effects of intrinsic pathway protease deficiencies on plasminogen-deficient mice.
Plasminogen (Plg)-deficient mice experience wasting and have decreased longevity due to disseminated fibrin deposition. We generated mice with combined deficiencies of Plg and coagulation factor IX (fIX) or XI (fXI) to determine the effects on the Plg null phenotype. Mice lacking Plg and fIX (Plg(-/-)/fIX-/-) have lower mortality at age 6 months than Plg(-/-)/fIX+/+ mice (15% and 67%, respectively) and less severe wasting, consistent with the importance of fIX in fibrin formation. In contrast, combined Plg and fXI deficiency (Plg(-/-)/fXI-/-) reduces life span (more than 90% mortality at 6 months) and is associated with leukocyte infiltration of the lungs and pulmonary fibrosis. These abnormalities are not seen in Plg-/- or Plg(-/-)/fIX-/- animals. Activated fXI is thought to function primarily as a fIX activator; however, our observation suggests that fXI may have functions in regulation of inflammation or tissue repair distinct from its role in coagulation.
Animals↗
Factor XIa induced activation of the intrinsic cascade in vivo.
Coagulation factor XI is a glycoprotein of the contact factor system. Its deficiency is associated with a highly variable bleeding tendency, thus a role in relation to hemostasis appears to exist. However, the importance of factor XI for stimulating intrinsic coagulation in vivo has not yet been determined. To study the procoagulant effects of human factor XIa in vivo, we infused the purified enzyme into normal chimpanzees (100 micrograms) in the absence or presence of the thrombin inhibitor rec-hirudin (1.0 mg/kg loading dose plus 0.3 mg/kg body wt continuous infusion). Factor XIa elicited an immediate activation of factors IX, X, and prothrombin, as measured by their respective activation fragments. However, whereas the activation of factors IX and X was immediate and shortlasting, (peak increments of 6- and 1.4-fold of baseline at 5 minutes after injection), the conversion of prothrombin gradually increased, reaching a summit of 6-fold baseline values after 60 min, and remaining elevated during the course of the experiments. Thrombin-antithrombin complexes also remained elevated during the study period. In the presence of hirudin, the initial activation of factors IX, X, and prothrombin was unchanged, however the further increment in prothrombin fragment F1 + 2 was markedly inhibited. These results demonstrate that factor XIa is a potential agonist of the intrinsic cascade in vivo, which activity is enhanced in the presence of thrombin.
Analysis of Variance↗
Amidolytic assay of factor V in human plasma.
An amidolytic assay was developed for measuring factor V in human plasma. Diluted plasma is incubated at 37 degrees C with lipid, Ca++, Taipan Snake Venom (Oxyuranus Scutellatus Scutellatus) and bovine prothrombin. The reaction is stopped after 4 min with EDTA. The content of factor V in samples is then determined by measuring the amidolytic activity of formed thrombin on synthetic chromogenic peptide substrate S-2238, H-D-Phe-Pip-Arg-pNA. The assay appears to be specific for factor V as: human congenitally deficient FV plasma gives no activity in the system, deficiency of factor II, VII, VIII, IX, X, XI or XII does not affect the determination of FV and no prothrombin is activated if the assay is run without venom. The correlation coefficient r between this amidolytic assay and a clotting assay was 0.91 (n = 20). The intra-assay coefficient of variation was 3.7% for the amidolytic method.
Calcium↗
Partial purification of plasma thromboplastin antecedent (factor XI) and its activation by trypsin.
A persistent puzzle in our understanding of hemostasis has been the absence of hemorrhagic symptoms in the majority of patients with Hageman trait, the hereditary deficiency of Hageman factor (factor XII). One proposed hypothesis is that alternative mechanisms exist in blood through which plasma thromboplastin antecedent (PTA, factor XI) can become active in the absence of Hageman factor. In order to test this hypothesis, the effect of several proteolytic enzymes, among them thrombin, plasma kallikrein, and trypsin, was tested upon unactivated PTA. PTA was prepared from normal human plasma by Ca(3)(PO(4))(2) adsorption, ammonium sulfate fractionation, and successive chromatography on QAE-Sephadex (twice). Sephadex-G150, and SP-Sephadex. The partially purified PTA was almost all in its native form, with a specific activity of 45-70 U/mg protein; the yield was about 10%. It contained no measurable amounts of other known clotting factors, plasmin, plasminogen, nor IgG. Incubation of PTA with trypsin generated potent clot-promoting activity that corrected the abnormally long clotting time of plasma deficient in Hageman factor or PTA but not in Christmas factor. This clot-promoting agent behaved like activated PTA on gel filtration (apparent molecular weight: 185,000) and was specifically inhibited by an antiserum directed against activated PTA. These data suggested that PTA can be converted into its active form by trypsin. PTA was not activated by thrombin, chymotrypsin, papain, ficin, plasmin, plasma kallikrein, tissue thromboplastin, or C. Trypsin converted PTA to its active form enzymatically. Whether trypsin serves to activate PTA in vivo is not yet clear.
Adsorption↗
Inactivation of factor XIa by plasma protease inhibitors: predominant role of alpha 1-protease inhibitor and protective effect of high molecular weight kininogen.
Factor XIa is a plasma protease that, by activating Factor IX, plays an important role in the early phase of the intrinsic pathway of blood coagulation. Four plasma protease inhibitors, alpha(1)-protease inhibitor, antithrombin III, C1-inhibitor, and alpha(2)-plasmin inhibitor, have been reported to inactivate human Factor XIa, but their quantitative contribution to the inactivation of Factor XIa in plasma has not been fully assessed. Using purified systems, we observed that the second-order rate constants for the reaction of Factor XIa with alpha(1)-protease inhibitor, antithrombin III, and CI-inhibitor were 4.08, 10, and 14.6 M(-1) min(-1) x 10(3), respectively. The pseudo-first-order rate constants, at plasma concentration of the inhibitors, were 1.86 x 10(-1), 4.68 x 10(-2), and 2.4 x 10(-2) min(-1), respectively. These kinetic data predict that alpha(1)-protease inhibitor should account for 68%, antithrombin III for 16%, and C1-inhibitor and the equipotent alpha(2)-plasmin inhibitor each for 8% of the total inhibitory activity of plasma against Factor XIa. The rate of inactivation of Factor XIa in various plasma samples specifically deficient in inhibitors was consistent with these predictions. Factor XI, the zymogen form of Factor XIa, circulates in plasma associated with the contact system cofactor, high molecular weight kininogen (HMW kininogen). Kinetic analysis indicated the existence of a reversible bimolecular Factor XIa-HMW kininogen complex with a dissociation constant (K(d)) = 0.17 muM. The light chain derived from HMW kininogen decreased the inactivation rate of Factor XIa by C1-inhibitor with a K(d) of 0.08 muM for a complex of Factor XIa and the light chain derived from HMW kininogen. The protective effect of HMW kininogen was confirmed by the finding that the inactivation rate of Factor XIa in kininogen-deficient plasma was increased over normal plasma. The present study confirms that alpha(1)-protease inhibitor is the major inhibitor of Factor XIa in plasma, and that the formation of a reversible complex between Factor XIa and HMW kininogen decreases the rate of inactivation of the enzyme by its inhibitors.
Antithrombin III↗
Plasma inhibitors of the Hageman factor dependent pathways.
The Hageman factor dependent pathways are influenced by several control proteins which modulate the extent of activation and biologic activity of these enzyme substrates (Fig. 1). C1 INH plays a prominent role by acting at the common initiating step for all three Hageman factor dependent systems and its deficiency produces disease in man. Alpha-2 macroglobulin appears to play an important role in the fibrinolytic sequence, having potent activity towards both plasminogen activator and plasmin. Antithrombin most prominently influences the state of activation of the coagulation sequence by regulating the enzymatic activities of activated Factors XI, IX and X and, most importantly, that of thrombin. Significantly, deficiency of antithrombin results in increased thrombosis in man.
Blood Coagulation↗
The formation of a thrombin-like material (TLM) following stimulation of leukocytes.
When thrombin, tissue thromboplastin or Russell's viper venom was added to a suspension of either lymphocytes or neutrophils containing normal plasma, aggregation of these cells ensued. The aggregate formed one gelatinous mass which was readily separable from the cell free supernatant, an aliquot of which caused platelet aggregation. This leukocyte derived platelet aggregatory substance had characteristics similar to thrombin but not AGEPC. When plasma deficient in Factor V was substituted for normal plasma, the platelet stimulatory substance was not produced. Substitution with plasma deficient in Factor VII, VIII, IX, X or XI was without effect. Thrombin clotting time measurements indicated a generation of activity, relative to thrombin, of about 3.0 U/5 X 10(6) cells.
Cell Aggregation↗
The animal models for hemorrhage and thrombosis in the neonate.
Animal models have added significantly to our understanding of adult hemorrhagic and thrombotic diseases. Few models, however, have been developed for studies of the hemostatic disorders in the fetus and newborn. This report reviews the current information on animal models of fetal and neonatal hemostasis. The requirements of a relevant model are addressed and previous studies using fetal and neonatal animal models are reviewed. A recommendation of a single animal for all studies of fetal and neonatal hemostasis is not possible. However, the lamb has been the most frequently studied and appears to provide relevant information regarding normal development and the factors which may adversely influence hemostasis in the fetus and newborn. Animal models, in contrast to in vitro experiments, provide a means of studying the entire spectrum of biologic consequences that results from a single experimentally induced alteration. In the "Introduction to the Study of Experimental Medicine" Claude Bernard commented "I not only conclude that experiments made on animals from the physiological, pathological, and therapeutic points of view have results that are applicable to theoretic medicine, but I think that without such comparative study of animals, practical medicine can never acquire a scientific character". In the area of blood coagulation, animal models have added significantly to our understanding of the pathophysiology of hemorrhage and thrombosis. There are animal models for both congenital and acquired bleeding disorders including factor VII, VIII, IX, X, XI, and fibrinogen deficiency; as well as von Willebrand's disease and disorders of platelet function.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Type C female hemophilia. (Hemophilia caused by "plasma thromboplastin antecedent" deficiency)].
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Factor XI↗
PLASMA THROMBOPLASTIN ANTECEDENT (FACTOR XI) IN THE NEONATE.
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Antifibrinolytic Agents↗
Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces.
Human blood coagulation factor XI was activated by either autoactivation or thrombin. These reactions occurred only in the presence of negatively charged materials, such as dextran sulfate (approximately Mr 500,000), sulfatide, and heparin. During the activation, factor XI was cleaved at a single Arg-Ile bond by thrombin or factor XIa to produce an amino-terminal 50-kDa heavy chain and a carboxyl-terminal 35-kDa light chain. This activation pattern is identical to that produced by factor XIIa. The addition of a small amount of thrombin and sulfatide to factor XII-deficient plasma produced shorter clotting times than when these agents were added to factor XI/factor XII combined-deficient plasma. These results suggest that the activation of factor XI by thrombin and possibly the autoactivation of factor XI proceed in plasma to lead fibrin clot formation. These reactions may have a role on an appropriate negatively charged surface in normal hemostasis.
Anions↗
Factor XI activation in a revised model of blood coagulation.
Coagulation factor XI is activated in vitro by factor XIIa in the presence of high molecular weight kininogen (HMWK) and a negatively charged surface. Factor XII deficiency is not associated with bleeding, which suggests that another mechanism for factor XI activation exists in vivo. A revised model of coagulation is proposed in which factor XI is activated by thrombin. In the absence of cofactors, thrombin is more effective (kcat/Km = 1.6 x 10(5)) than factor XIIa (1.7 x 10(4)) in activating factor XI. Dextran sulfate enhances activation of factor XI by thrombin 2000-fold; part of this effect is due to autoactivation of factor XI by activated factor XI.
Blood Coagulation↗
A comparison of two APTT reagents which use silica activators.
The Ortho activated partial thromboplastin time (APTT) reagent, Thrombosil 1 (TS), was compared to the General Diagnostics automated APTT reagent (GD). TS produced more precise results over a 38-day period of testing a normal control plasma, indicating that the upper limit of the normal range could be more precisely set with TS. This normal range was better represented if the normal values with both reagents were logarithmically transformed before calculating the mean +/- 2 SD. TS was more sensitive to plasma which had been heparinized in vitro. This was also demonstrated in vivo by the testing of 100 plasmas from heparinized patients. On testing of in-vitro dilutions of normal plasma with factor-deficient plasmas, TS was more sensitive to decreasing levels of factors VIII, IX and XI but less sensitive to decreasing factor XII. This was demonstrable in vivo in 71% of cases with plasmas from factor-deficient patients. GD was more sensitive to the lupus anticoagulant in most cases.
Blood Coagulation Factors↗