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PubMed1990

Surface-dependent reactions of the vitamin K-dependent enzyme complexes.

During the past 20 years contributions from many laboratories have led to the development of isolation procedures, delineation of primary structures, and more recently, to the expression of recombinant proteins associated with the coagulation cascade. In general, studies of coagulation proteins under defined conditions have demonstrated the prescience of Davie and Ratnoff and MacFarlane in their proposals of the coagulation cascade. The more recent discovery of thrombomodulin by Esmon et al has led to the identification and characterization of components of the vitamin K-dependent anticoagulant pathway. In this review we have attempted to analyze and compare the functional properties of each of the vitamin K-dependent enzyme complexes associated with the procoagulant and anticoagulant phases of blood clotting. Although dissimilarities exist, the vitamin K-dependent complexes have analogous requirements and appear to function with a common general mode of organization. Membrane-bound cofactors serve as anchoring sites for the appropriate membrane-binding enzymes. This process localizes the complex on the membrane surface and increases the catalytic efficiency for substrate utilization. Complex formation provides extraordinary improvements in the catalytic efficiency for the complexes as compared with their soluble enzyme components. Membrane-bound complexes provide a mechanism that can be regulated at a site by membrane presentation, zymogen activation, and cofactor activation or presentation. The kinetic constants obtained for the various coagulation reactions determined in vitro provide some insights into how these pathways may function in vivo. The catalytic efficiency (kcat/Km) for factor X activation by factor VIIIa/factor IXa is far in excess of the catalytic efficiency of activation of factor X by tissue factor/factor VIIa (Table 3). This may provide a rational interpretation for the observation that patients with hemophilia A and B bleed even though they appear to have an alternative pathway to factor X activation. In addition, tissue factor is not ordinarily presented by the vascular tissue that has direct access to blood. However, it appears that extravascular constitutive tissue factor is available once the blood vessel becomes disrupted. The efforts to identify the initiating reactions of the blood coagulation process have not been unambiguously successful. We conclude that factor VII is most likely a zymogen, just as are the other proenzymes of the blood clotting process. In addition, it is difficult to rationalize the importance of the intrinsic pathway of coagulation involving factor XII, prekallikrein, and high molecular weight kininogen since the congenital absence of any one of these factors does not result in abnormal bleeding.(ABSTRACT TRUNCATED AT 400 WORDS)

Blood Coagulation↗
PubMed1996

Gemfibrozil reduces thrombin generation in patients with combined hyperlipidaemia, without influencing plasma fibrinogen, fibrin gel structure or coagulation factor VII.

A double-blind, placebo-controlled, cross-over study was conducted in 21 men with combined hyperlipoproteinaemia to examine if lipid-lowering treatment with gemfibrozil (10-12 weeks) affects blood coagulation and fibrin gel structure at rest or during mental stress. Gemfibrozil lowered plasma triglycerides by 57 +/- 4%, whereas high density lipoprotein (HDL) cholesterol increased by 22 +/- 5%. Gemfibrozil lowered the triglyceride content of low density lipoprotein (LDL). Gemfibrozil reduced the plasma concentrations of thrombin-antithrombin complex (TAT) and prothrombin fragment F1 + 2 (F1 + 2), both at rest and during mental stress. However, there were no effects of gemfibrozil treatment on the plasma concentrations of fibrinogen, factor VII antigen, activated factor VII (VIIa) or activated factor XII (XIIa), or on fibrin gel structure. Acute mental stress per se did not influence coagulation factors, reaction products or fibrin gel structure, or their responses to the study drug. Thus, gemfibrozil reduced thrombin generation in men with combined hyperlipoproteinaemia, without influencing the plasma levels of fibrinogen, VIIa and XIIa, or fibrin gel structure. Attenuation of thrombin generation may contribute to the primary-preventive effects of gemfibrozil on coronary heart disease.

Adult↗
PubMed1973

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↗
PubMed1996

Effect of heparin on the activation of factor XI by fibrin-bound thrombin.

Fibrin-bound thrombin is protected from inactivation by antithrombin III, while its coagulant potential is retained. In the presence of heparin, ternary complexes between thrombin, fibrin and heparin are formed. In these complexes the coagulant activity of thrombin is retained, whereas the anticoagulant activity of fibrin-bound heparin is neutralized. The limited effectiveness of heparin in the prevention of both venous thrombosis and coronary reocclusion is probably related to the protective effect of fibrin on the inactivation of thrombin by anti-thrombin III. Recently, it has been shown that factor XI can be activated by thrombin, resulting in the generation of additional thrombin via the intrinsic pathway. This additional thrombin is capable of stabilizing the clot by protecting it from fibrinolysis. We studied the effect of heparin on the activation of factor XI by fibrin-bound thrombin. First, we used fibrin monomers coupled to Sepharose to which thrombin and unfractionated heparin (UFH) were bound. Factor XI activation by thrombin was the same in the presence of fibrin-Sepharose or control-Sepharose. The addition of heparin (0.1 U/ml) resulted in a 91 and 15-fold enhancement in the presence of control-Sepharose and fibrin-Sepharose, respectively. Next, we added complexes of heparin, thrombin and fibrin monomer to factor XII and XI double-deficient plasma in the presence or absence of a reconstituting amount of factor XI. In the presence of factor XI, additional fibrin formation was observed indicating that factor XI activation by thrombin in complex with fibrin and heparin can take place in plasma. We then studied the effect of other heparin-like anticoagulants on the thrombin-mediated factor XI activation. UFH enhanced thrombin-mediated factor XI activation 68-fold, LMWH (low molecular weight heparin, Fragmin) 12-fold, danaparoid (Orgaran) 3-fold, while the pentasaccharide ORG 31540 did not result in an enhancement. Binding studies of these anticoagulants to fibrin-Sepharose showed that LMWH bound with approximately the same affinity as UFH, while danaparoid and the pentasaccharide did not bind to fibrin. We conclude that fibrin-bound thrombin is capable of factor XI activation. Furthermore, heparin bound in a complex with fibrin can act as a cofactor for this activation. This factor XI activation capacity may play a role in the limited effectiveness of heparin. Provided that thrombin-mediated factor XI activation plays an important role in vivo, danaparoid and especially the pentasaccharide may be better anticoagulants than UFH and LMWH.

Blood Coagulation↗
PubMedDate not supplied

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↗
PubMed1988

An overview of hemostasis.

The normal hemostatic system is complex yet exquisitely well regulated. Interrelationships exist between responses of the vasculature, circulating platelets, coagulation proteins, and fibrinolytic mechanism. These relationships serve to limit blood loss, preserve tissue perfusion, and stimulate local repair processes. Natural inhibitors of coagulation and fibrinolysis modulate these systems to prevent uncontrolled thrombosis or hemorrhage following pathologic stimuli. Vascular endothelial cells play an important role in the maintenance of a thromboresistant luminal interface with circulating cells and proteins. Normal hemostasis also requires the synthetic, metabolic, and repair processes of the vascular endothelium. The initial vascular response to injury produces brief vasoconstriction and exposes subendothelial substances that attract circulating platelets and activate coagulation proteins. Platelets respond by adherence and aggregation at the site of injury, with subsequent release of substances that mitigate blood loss. Platelet adherence to collagen requires von Willebrand's factor, fibrinogen, fibronectin, and specific glycoprotein receptors on platelet surfaces. Platelet-to-platelet interactions (aggregation) recruit additional platelets to the primary hemostatic plug. Aggregation requires fibrinogen, energy, and calcium. Release of ADP, serotonin, and the contents of intracellular granules as well as generation of prostaglandins prepares platelet surfaces for reactions with the coagulation proteins. Activation of the intrinsic or extrinsic coagulation pathway, or of both, causes formation of fibrin from fibrinogen by means of an elaborate and intricate system that also entraps platelets and activated coagulation proteins. The intrinsic system is activated by the contact of factor XII with a negatively charged surface, most likely collagen. Through a series of reactions with prekallikrein, HMWK, and factors XI, IX, and VIII, the common coagulation pathway is propagated. The extrinsic, or tissue factor, system stimulates both the common pathway and factor IX the intrinsic pathway. Discovery of this stimulation of the intrinsic pathway by factor VII in the extrinsic pathway has stimulated reassessment of the biologic importance of the extrinsic system. The common pathway includes factors X and V and causes thrombin to convert fibrinogen to fibrin. Calcium and platelet phospholipids are substances that have important roles in steps in the coagulation scheme. Once fibrin is formed, factor XIII interacts with the substance, providing a stabilizing effect.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Comparative study of intranasal, subcutaneous and intravenous administration of desamino-D-arginine vasopressin (DDAVP).

This study was performed to evaluate the influence of different routes of administration on the efficacy of DDAVP treatment. Ten healthy volunteers received DDAVP intranasally (i.n.), subcutaneously (s.c.) and intravenously (i.v.) in a randomized cross-over trial. Factor XII and high molecular weight (HMW)-kininogen levels increased only slightly after DDAVP administration. The mean increase of factor VIII: C was 3.1 (i.v.), 2.3 (s.c.), and 1.3 (i.n.) - fold over baseline. Ristocetin cofactor (von Willebrand factor antigen) increased 3.1 (2.5), 2.0 (2.3) and 1.2 (1.2) - fold over baseline mean values after i.v., s.c. and i.n. DDAVP, respectively. The half-disappearance time of factor VIII and von Willebrand factor (vWF) after DDAVP ranged from five (factor VIII:C) to eight hours (vWF). The mean increase of fibrinolytic activity was more pronounced after i.v. DDAVP. The antidiuretic effect was moderate with no apparent differences between the routes of application. This study provides further evidence that both i.v. and s.c. DDAVP administration result in an appropriate and reliable stimulation of haemostasis. An additional advantage of s.c. administration is its suitability for home treatment.

Adult↗
PubMed1984

A unique precipitating autoantibody against plasma thromboplastin antecedent associated with multiple apparent plasma clotting factor deficiencies in a patient with systemic lupus erythematosus.

A 42-yr-old woman with systemic lupus erythematosus without bleeding diathesis developed a prolonged activated partial thromboplastin time that was not corrected by normal plasma. An inhibitor that acted rapidly and inactivated 0.5 U/ml plasma thromboplastin antecedent (PTA, factor XI) at a 1:200 plasma dilution was demonstrated. In addition to a low titer of PTA (less than 0.01 U/ml), plasma assayed at 20-fold dilution also showed low titers of Hageman (factor XII, 0.02 U/ml), Fletcher (plasma prekallikrein, 0.02 U/ml), and Fitzgerald (high molecular weight kininogen, less than 0.01 U/ml) factors. The titer of these factors, except PTA, returned to normal upon further plasma dilution or upon removal of the inhibitor by protein A adsorption. Thus, the inhibitor appeared to interfere with these clotting factor assays, possibly by inactivating PTA in the substrate plasmas in the test system. Its specificity was further confirmed. The inhibitor did not interfere with surface-induced proteolytic cleavage of Hageman factor. Surface-induced generation of plasma kallikrein activity (amidolysis of H-D-pro-phe-arg-pNa and cold-promoted factor VII activity enhancement) requires only Hageman, Fletcher, and Fitzgerald factors and was normal. Reactions requiring all 4 contact phase factors, including PTA, such as surface-induced generation of plasmin activity (amidolysis of H-D-val-leu-lys-pNa) and activated Christmas factor (factor IXa) activity, were defective. Furthermore, the inhibitor bound to agarose-protein A inactivated and removed PTA selectively from normal plasma. The inhibitor was an IgG-lambda autoantibody that precipitated PTA. The inactivated activated PTA (factor XIa) without the requirement for an additional cofactor. Furthermore, it inhibited surface-induced activation of PTA by interfering with its proteolytic cleavage upon glass surface exposure and with its binding onto the reactive surfaces.

Adult↗
PubMed1981

An improved method for evaluation of blood coagulation in heparinized blood.

A simple method designed to allow coagulation studies in heparinized blood was evaluated. Citrated plasma containing heparin was incubated with an anion-exchange resin commercially available in tablet form (Heparsorb). After centrifugation of the mixture, coagulation studies were carried out on the supernatant plasma. One heparin neutralizer (HN) tablet was capable of removing as much as 43 units of heparin from 1 ml plasma within 10 min of incubation. When normal plasma was exposed to the heparin neutralizer, little or no change in the activities of clotting factors XII, XI, VIII, VII, X, V, and II was observed. However, the resin caused a substantial (44%) loss of factor IX-activity from normal plasma. This loss of factor IX-activity was not observed with plasma from patients receiving coumadin therapy. The results of coagulation tests (aPTT, PT, TT) and determination of fibrinogen/fibrin degradation products performed with HN-treated plasmas from nine patients receiving heparin therapy for thromboembolic disease and seven patients undergoing cardiopulmonary bypass operations were virtually identical to those obtained for the same persons before heparin was administered. The method, which is suitable for the routine clinical laboratory, may be useful in the hemostatic evaluation of critically ill patients who experience bleeding complications while receiving heparin therapy, in the laboratory control of coumadin therapy during the heparin-coumadin overlap period, and in the rapid identification of heparin contamination of blood specimens as a cause of an unexplained aPTT prolongation.

Blood Coagulation Tests↗
PubMed1984

The multiple coagulopathies of biliary atresia.

Detailed coagulation studies were done prospectively on 43 patients with biliary atresia who had undergone Kasai operation (hepatic portoenterostomy). Patients were divided into three groups based on levels of factor V, factor II, and Echis II and/or response to vitamin K: no coagulopathy (46.5% of patients); coagulopathy of liver disease (30.2% of patients); and coagulopathy of vitamin K deficiency (23.3% of patients). Patients with the coagulopathy of liver disease had significantly lower levels of factors XII, V, and antithrombin III as well as longer thrombin times than patients with no coagulopathy or vitamin K deficiency. Factor V levels were decreased only in patients with more advanced liver disease; normal levels of factor V were not usually helpful in differentiating liver disease and vitamin K deficiency. The prothrombin time, factor VII-X levels, and factor II levels were significantly different for all three groups; the most abnormal values occurred in the vitamin K-deficient group. Comparison of the Echis II level to factor II coagulant activity was helpful in deciding whether a coagulopathy was due to liver disease, vitamin K deficiency, or both. Factor VIII levels were elevated in all groups. Factor VIII coagulant activity was significantly higher by the two-stage (TGT) method than by the one-stage (PTT) method. Hypersplenism causing neutropenia and thrombocytopenia was commonly seen after the age of 5 years. Vitamin E deficiency was more common than vitamin K deficiency; however, all vitamin K-deficient patients were vitamin E deficient. Coagulation status correlated well with hepatobiliary scan data, but not serum bilirubin levels. Recommendations for treatment of patients with vitamin K deficiency and/or liver disease are discussed.

Bile Duct Diseases↗
PubMed1992

Hematological problems during the use of cardiac assist devices: clinical experiences in Japan.

Hematological changes occurring during use of left ventricular assist devices (LVADs) were evaluated in 3 patients suffering from postcardiotomy cardiogenic shock. LVAD treatment ranged from 6 to 9 days. During the procedure, no anticoagulants were used in the first two cases, while in the third case, a protease-inhibiting agent, nafamostat mesilate (FUT-175), was used. In the first two cases without any anticoagulants, fibrinopeptide A (FPA) and thrombin-antithrombin III complex (TAT) increased markedly over the course of LVAD treatment, suggesting the excessive activation of the coagulatory system. The fibrinolytic system also became activated during LVAD treatment as was indicated by a marked increase in FDP-D-dimer and alpha 2 plasmin inhibitor-plasmin complex (PIC). Continual decreases observed in Factor XII and prekallikrein indicate that the coagulofibrinolytic activation occurring during LVAD treatment is presumably the result of contact activation of these factors due to interaction of blood with the internal surface of the LVAD. In the third case with FUT-175, both coagulation and fibrinolysis were successfully maintained at minimum levels as was demonstrated by the extremely low levels of these molecular markers. There was also no significant consumption of any contact factors. FUT-175 looks promising as an anticoagulant during the use of cardiac assist devices.

Aged↗
PubMed1967

Diagnosis of haemophilia: use of an artificial factor-VIII-deficient human plasma system.

An artificial clotting system deficient in factor VIII has been made from normal human plasma. Factors XII and XI are supplied as ;activation product'. An eluate from Al(OH)(3), which has been incubated with normal plasma, supplies factors X and IX in their ;plasma' (unactivated) form with II. Factor V is provided as the supernatant after the Al(OH)(3)- treated plasma has been precipitated at one-third saturation with (NH(4))(2)SO(4). Fibrinogen is freed of factor VIII by freezing and thawing a lyophylized preparation and then added. Of these, activation product and the fibrinogen may be prepared in advance and stored frozen, and the eluate and supernatant may be made on the day of testing. A phospholipid source and CaCl(2)-solution are also required. In use, a patient's and a control plasma are first diluted in a mixture of the eluate, supernatant, and fibrinogen solution, and clotting times are recorded after completing the system by adding the phospholipid, activation product, and calcium chloride. The clotting times from the mixtures containing the patient's and the control plasmas may then be compared.

Blood Coagulation Tests↗
PubMed1992

Fibrinogen blocks the autoactivation and thrombin-mediated activation of factor XI on dextran sulfate.

The intrinsic pathway of blood coagulation is activated when factor XIa, one of the three contact-system enzymes, is generated and then activates factor IX. Factor XI has been shown to be efficiently activated in vitro by surface-bound factor XIIa after factor XI is transported to the surface by its cofactor, high molecular weight kininogen (HK). However, individuals lacking any of the three contact-system proteins--namely, factor XII, prekallikrein, and HK--do not suffer from bleeding abnormalities. This mystery has led several investigators to search for an "alternate" activation pathway for factor XI. Recently, factor XI has been reported to be autoactivated on the soluble "surface" dextran sulfate, and thrombin was shown to accelerate the autoactivation. However, it was also reported that HK, the cofactor for factor XIIa-mediated activation of factor XI, actually diminishes the thrombin-catalyzed activation rate of factor XI. Nonetheless, it was suggested that thrombin was a more efficient activator than factor XIIa. In this report we investigated the effect of fibrinogen, the major coagulation protein in plasma, on the activation rate of factor XI. Fibrinogen, the preferred substrate for thrombin in plasma, virtually prevented autoactivation of factor XI as well as the thrombin-mediated activation of factor XI, while having no effect on factor XIIa-catalyzed activation. HK dramatically curtailed the autoactivation of factor XI in addition to the thrombin-mediated activation. These data indicate that factor XI would not be autoactivated in a plasma environment, and thrombin would, therefore, be unlikely to potentiate the activation. We believe that the "missing pathway" for factor XI activation remains an enigma that warrants further investigation.

Dextran Sulfate↗
PubMed1992

Twenty-four-hour heparin-free veno-right ventricular ECMO: an experimental study.

Platelets and coagulation factors were studied during 24-hour heparin-free veno-right ventricular extracorporeal membrane oxygenation (ECMO) in 6 healthy pigs. An endpoint attached and covalently bonded heparin-coated ECMO system was used in these experiments. The veno-right ventricular ECMO supplied the total lung function of the animals, and after 24 hours, all the animals were successfully weaned from ECMO. Lung function and central hemodynamics were not affected by the procedure. Because all the animals showed a significant reduction in plasma volume, the concentration of measured coagulation variables was corrected both for plasma volume changes and for hemodilution. The platelet count and the plasma-free hemoglobin level were not significantly altered by ECMO. Similarly, the prothrombin complex, antithrombin, thrombin-antithrombin complex, factor XII, and the urinary excretion of 2,3-dinor-thromboxane B2 were not significantly altered. Fibrinogen and fibrin monomer increased significantly, whereas von Willebrand factor was significantly decreased after ECMO. In summary, 24-hour heparin-free veno-right ventricular total extracorporeal lung assistance does not affect the platelets and the coagulation system significantly in healthy juvenile pigs.

Animals↗
PubMed1999

Multicentre evaluation of combined prothrombotic defects associated with thrombophilia in childhood. Childhood Thrombophilia Study Group.

UNLABELLED: To evaluate the role of multiple established and potential causes of childhood thrombophilia, 285 children with a history of thrombosis aged neonate to 18 years (first thrombotic onset) were investigated and compared with 185 healthy peers. APC-resistance (FV:Q506), protein C, protein S, antithrombin, heparin cofactor II (HCII), histidine-rich glycoprotein (HRGP), and prothrombin (F.II), factor XII (F.XII), plasminogen, homocysteine and lipoprotein (a) (Lp(a)) were investigated. In 59% of patients investigated one thrombotic defect was diagnosed, 19.6% showed two thrombotic risk factors, while in 21.4% of children investigated no risk factor could be identified. Single defects comprised established causes of inherited thrombophilia: FV:Q506 (homozygous n = 10, heterozygous n = 69), protein C (homozygous n = 1; heterozygous n = 31), heterozygous type I deficiency states of protein S (n = 7), antithrombin (n = 7) and homocystinuria (n = 6); potentially inherited clotting abnormalities which may be associated with thrombophilia: F.XII (n = 3), plasminogen (n = 2), HCII (n = 1), increased HRGP (n = 4); new candidate risk factors for thrombophilia: elevated plasma levels of Lp(a) (n = 26), F.II (n = 1). Heterozygous FV:Q506 was found in combination with heterozygous type I deficiency states of protein C (n = 2), protein S (n = 13), antithrombin (n = 8) and HCII (n = 1), increased Lp(a) (n = 13), and once each with elevated levels of F.II, moderate hyperhomocysteinemia, fibrinogen concentrations > 700 mg/dl and increased HRGP. In addition to the association with FV:Q506, heterozygous protein C type I deficiency was combined with deficiencies of protein S (n = 2), antithrombin (n = 1), and increased Lp(a) (n = 3). One patient showed protein C deficiency along with familially increased von Willebrand factor > 250%. Besides coexistence with FV:Q506 and protein C deficiency, protein S deficiency was combined with decreased F.XII and increased Lp(a) in one subject each. Furthermore, we found combinations of antithrombin deficiency/elevated Lp(a), hyperhomocysteinemia/Lp(a), deficiency of HCII/plasminogen, and plasminogen deficiency along with increased Lp(a) each in one. Increased prothrombin levels were associated with fibrinogen concentrations > 700 mg/dl and with HCII deficiency in one child each. Carrier frequencies of single and combined defects were significantly higher in patients compared with the controls. CONCLUSION: In conclusion, data of this multicentre evaluation indicate that paediatric thromboembolism should be viewed as a multifactorial disorder.

Adolescent↗
PubMed1997

Factor XIIa activation of plasminogen is enhanced by contact activating surfaces and Zn2+.

The native form of plasminogen is Glu-plasminogen, which by plasmin cleavage gives Lys-plasminogen. Lys-plasminogen is a considerably better substrate compared with Glu-plasminogen for plasminogenolytic enzymes. The contact activation of the intrinsic pathway of coagulation consisting of factor XII, prekallikrein and high Mr kininogen has been implicated to play a role in the intrinsic fibrinolysis. Here activation of Glu- and Lys-plasminogen by factor XIIa in the absence of prekallikrein/kallikrein and high Mr kininogen was studied in a purified system by the generation of amidolytic activity towards pyroGlu-Phe-Lys-pNA (S-2403), a chromogenic substrate of plasmin. A slow activation rate of both Glu- and Lys-plasminogen by factor XIIa was enhanced approximately 60-fold in the presence of Zn2+ and a negatively charged surface. 6-Aminohexanoic acid further enhanced the activation of Glu-plasminogen but inhibited the activation of Lys-plasminogen. The presence of a specific factor XIIa inhibitor completely prevented the generation of plasmin amidolytic activity indicating that activation was mediated by proteolytical cleavage, although this could not be proven by Western-blotting. Physiological concentration of factor XIIa was as more efficient than soluble u-PA to lyse fibrin as a result of activation of Glu-plasminogen. This did not require the presence of Zn2+ or sulfatide.

Aminocaproic Acid↗
PubMed1996

[Evaluation of the factor XIIa assay kit].

The assay for activated coagulation factors has recently been considered to be a useful tool for detecting hypercoagulable state. Measurement of activated factor XI and alpha 1 antitrypsin complex developed by us is the only one measure for detecting contact phase hypercoagulation. The ACTIVATED FACTOR XII kit (Shield Diagnostics) has recently been commercially available, and the reference range was reported in the instruction manual. However, because the recovery rate of purified factor XIIa (XIIa) in normal pooled plasma by this assay kit was strikingly decreased, the effects of inhibitors in plasma, such as low molecular weight serine proteinase inhibitor (diisopropyl fluoro-phosphate, DFP), the specific inhibitor for XIIa (corn trypsin inhibitor, CTI), the main inhibitor for XIIa (C1 inhibitor, C1I) were examined. These three inhibitors and XIIa were incubated for 18 hours, then the XIIa levels of these complexes and the recovery rate in the normal pooled plasma were assayed by this assay kit. The recovery ratios in the normal pooled plasma were; DFP-XIIa 82%, CTI-XIIa 63%, and C1I-XIIa 0%, XIIa without inhibitor 7%. These results suggest that this XIIa kit does not reflect the levels of complexed form of XIIa and inhibitors in plasma samples.

Adult↗