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PubMedDate not supplied

Coagulation abnormalities in type 1 Gaucher disease in children.

Gaucher disease is the most prevalent inherited lysosomal storage disorder caused by deficiency of beta-glucocerebrosidase enzyme. Clinically, 3 forms of Gaucher disease are recognized, of which type 1 is the mild to moderately severe, slowly progressive, nonneuropathic form. Bleeding disorders in Gaucher disease are believed to be due to thrombocytopenia but there may be additional factors that influence coagulation and fibrinolysis in Gaucher disease patients. The aim of the present work was to study some coagulation parameters in the Egyptian children with type 1 Gaucher disease. Five newly diagnosed patients and another 5 patients on enzyme replacement therapy (ERT) were enrolled in the study. Their coagulation profile, including coagulation factors, was evaluated. The results showed that in newly diagnosed cases factors II and VII were deficient in 40%, factor V was deficient in 20%, and all the cases had low levels of serum fibrinogen. In patients on ERT, factors VII and VIII were deficient in 60%, factor XI was deficient in 40% and factors V, X, and XII were deficient in 20% of cases. In conclusion, Egyptian patients with type 1 Gaucher disease, whether newly diagnosed or receiving enzyme replacement therapy, experience coagulation factor abnormalities regardless the clinical expression of bleeding diathesis. This should be taken into consideration before these patients are subjected to surgery for, e.g., splenectomy, which is common in these patients.

Blood Coagulation Disorders↗
PubMed1983

Initiation of contact activation by sulfatides.

Low amount of sulfatides initiated intrinsic coagulation and the appearance of kallikrein activity in normal human plasma. The initiation of procoagulant and kallikrein amidolytic activity was dependent on the presence of Factorr XII, high molecular weight kininogen and prekallikrein. Because the activated partial thromboplastin clotting times in prekallikrein deficient plasma approach normal values upon prolonged incubation with kaolin, this phenomenon was studied and found to be even more pronounced in the presence of sulfatides. Shortening of the clotting time was essentially completed in 5 min in the presence of sulfatides whereas a pre-incubation of 15 to 20 min was required in the presence of kaolin. The limited proteolysis of 125I-Factor XII in plasma during incubation was more rapid and more extensive in the presence of sulfatides than in the presence of kaolin. Factor XII cleavage in prekallikrein deficient plasma was completed in less than 5 min in the presence of sulfatides and in less than 15 min in the presence of kaolin. Thus, the appearance of Factor XII-dependent coagulant activity correlates with the limited proteolysis of Facto XII when normal or prekallikrein deficient plasma is activated by sulfatides or by kaolin. These observations are consistent with the hypothesis that Factor XII is cleaved in plasma to generate maximal Factor XIIa activity.

Animals↗
PubMed1989

Apolipoprotein B-100 of plasma low density lipoproteins undergoes proteolysis by contact activation factors when plasma is treated with dextran sulfate-500-MgCl2.

Human plasma low density lipoproteins (LDL) isolated by ultracentrifugation showed a single band corresponding to apolipoprotein B-100 (apoB-100) by SDS-gradient gel electrophoresis (GGE). In turn, apoB-100 of LDL precipitated from plasma by dextran sulfate-500 (DS)-MgCl2 exhibited several bands indicative of a degradative process. The degradation was more extensive at 0 degrees C than at either 23 degrees C or 37 degrees C, and appeared to be related to a protease activity that cleaved both the synthetic peptide, Z-Phe-Arg-7-amido-4-methylcoumarin (Z-Phe-Arg-AMC) and apoB-100. Proteolysis was proportional to the DS added to the plasma, was prevented by the kallikrein inhibitor, D-Phe-L-Phe-L-Arg-CHCl2, and was significantly decreased in plasma specimens of patients with either factor XII or prekalikrein deficiency. LDL pre-purified by ultracentrifugation and then precipitated by DS in the absence of plasma exhibited no proteolysis. However, proteolysis was observed when LDL interacted with kallikrein. The two main apolipoproteins of HDL3, apoA-I and apoA-II, were not affected by this proteolytic process. We interpret the results to indicate that the negatively charged surface provided by DS accelerates in plasma the autoactivation of factor XII and the activation of prekallikrein, resulting in an increase of the effective concentration of kallikrein and possibly other proteases and proteolysis of LDL-apoB-100. The higher degree of the DS-induced proteolysis of apoB-100 at 0 degrees C than at 23 degrees C is likely the consequence of enhanced autoactivation of factor XII and a decreased efficiency of plasma inhibitors, such as C1-inhibitor. We speculate that the proteolysis of apoB-100 induced by DS is not limited to this polyanion, but may also be the property of other negatively charged agents, particularly at cold temperatures.

Apolipoprotein B-100↗
PubMed1979

Nonplasminogen-dependent protease in human plasma.

Equal volumes of plasma and 0.3 M K2HPO4, pH 7.4, were mixed, diluted 20-fold, and adjusted to pH 5.2. After incubation at 37 degrees C for 30 min, the euglobulin percipitate, redissolved in 0.1 M K2HPO4, pH 7.4, developed caseinolytic activity (0.05 CTA U/ml). Na2HPO4 or NaCl of similar ionic strength could replace K2HPO4. The pH optimum of the protease was 6.5, activity falling off sharply below pH 6.0 and above 7.4. The proteolytic activity was inhibited by diisopropylphosphofluoridate and by pancreatic trypsin inhibitor, but was not inhibited by soybean trypsin inhibitor. The activity was not due to plasmin, contact activation, or coagulation factors, since it was fully generated in plasminogen-depleted, factors XII, XI, VII deficient, and prekallikrein-deficient plasmas. Purified Cl-esterase was not caseinolytic in our system. Redissolved euglobulin precipitate prepared from normal plasma without salt addition could serve as starting material for the generation of caseinolytic activity, as could serum, indicating that the Hageman factor cofactor and thrombin are not required. The protease had no detectable procoagulant or fibrinolytic activity.

Chemical Precipitation↗
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↗
PubMed1987

Detection of activation of the contact system of coagulation in vitro and in vivo: quantitation of activated Hageman factor-C-1-inhibitor and kallikrein-C-1-inhibitor complexes by specific radioimmunoassays.

Radioimmunoassays (RIAs) for the detection of C-1-inhibitor (C-1-Inh) complexed to either kallikrein or activated Hageman factor (factor XIIa) are described. Kallikrein-C-1-Inh or factor XIIa-C-1-Inh complexes were bound to Sepharose to which monospecific antibodies against (pre)kallikrein or factor XII, respectively, were coupled. Bound complexes were subsequently detected by an incubation with affinity purified 125I-labeled antibodies against C-1-Inh. These RIAs were used to detect activation of the contact system of coagulation in vitro and in vivo. Addition of dextran sulfate (DXS) (20 micrograms/ml) to fresh plasma resulted at 37 degrees C in the rapid generation of amidolytic kallikrein activity, which was maximal after 1 to 2 min of incubation and subsequently decreased within a few minutes. The generation of kallikrein activity coincided with the appearance of both kallikrein-C-1-Inh and factor XIIa-C-1-Inh complexes. However, in contrast to kallikrein activity, both types of complexes remained detectable in the incubation mixtures during the incubation period. Experiments with purified kallikrein. C-1-Inh and partly purified beta-factor XIIa, and activation experiments in plasmas deficient in either factor XII or prekallikrein, demonstrated the specificity of both RIAs. The minimal amount of DXS that resulted in the generation of measurable amounts of both types of complexes in plasma was 2-3 micrograms per ml. Similar experiments with kaolin showed that with limiting amounts of activator (1-2 mg/ml), only kallikrein-C-1-Inh complexes were detected in plasma. When larger amounts of kaolin were added to plasma, factor XIIa-C-1-Inh complexes were additionally detected in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Coagulation↗
PubMed2001

Recurrent pregnancy loss: etiology of thrombophilia.

Congenital and acquired thrombophilia are associated with an increased risk of pregnancy-associated venous thrombosis and fetal loss. Two hundred eighty-nine patients with a history of recurrent spontaneous abortion were subjected to screening examinations for the etiology of these abortions. Endocrine abnormality (28.0%), uterine abnormality (10.4%), autoimmune diseases (1.4%), antiphospholipid antibody syndrome (4.5%), and balanced type chromosome translocation (4.2%) were found as underlying causes of recurrent abortions, and the remaining 55.0% of the 289 patients were classified as having an unexplained etiology. Congenital thrombophilia such as protein C (PC) deficiency, protein S (PS) deficiency, antithrombin deficiency, and factor V Leiden mutation was not frequently detected; only one patient had PS deficiency. A reduced factor XII activity was found at a frequency of 4.2%. The frequency of methylene tetrahydrofolate reductase gene C677T mutation in recurrent aborters (0.38) was the same as that found in a fertile control group. Although the prevalence of anti-beta2-glycoprotein I antibody (abeta2-GPI) syndrome was very low (1.7%), patients with a high titer of immunoglobulin G (IgG) class abeta2-GPI, despite anticoagulation therapy, experienced severe fetomaternal complications in subsequent pregnancies. The rate (13.8%) of positive tests for serum IgA class abeta2-GPI in patients with unexplained etiology was higher than that in the controls (0%) (P < .05). We conclude that congenital thrombophilia is rare in Japanese patients who had experienced consecutive spontaneous abortions.

Abortion, Habitual↗
PubMed2001

In vitro factor XI activation mechanism according to an optimized model of activated partial thromboplastin time test.

Whether the in vitro activation of factor XI in plasma is mediated by thrombin or by auto-activation remains a controversial question. In this context, we have simulated theoretical activated partial thromboplastin time (aPTT) by means of a program based on a body of 22 essential elementary reactions implemented with rate constants quoted in current literature. To meet self-consistency in input data issued from varying sources, the results were optimized using the simplex treatment. The performance of the model was systematically evaluated considering the extent of the deviations observed between predicted aPTT and laboratory measurements conducted on normal and factor VIII, IX, XI and XII single-factor deficient plasma. The influence of the auto-activation or thrombin-mediated activation of factor XI on these aPTTs was tested separately after insertion of these reactions in the model. According to the best fits, a mechanism accounting for an auto-activation reaction of activated factor XI rather than a positive feedback reaction mediated by thrombin seemed more likely. Based on this conclusion, a chart of self-consistent rate constant values accounting for the intrinsic pathway of coagulation under static conditions is proposed.

Blood Coagulation↗
PubMed1994

Activation of blood clotting factors by microbial proteinases.

There are very few reports on the involvement of bacterial proteinases on the blood clotting system using both human plasma and purified clotting factors. We studied whether microbial proteinases from the opportunistic pathogens Candida albicans, Pseudomonas aeruginosa and Serratia marcescens activate the blood clotting cascade by using normal human plasma, human plasmas deficient in clotting factor XII or X, and also by using purified clotting factors XII, X and prothrombin. All proteinases tested activated either clotting factor XII or prothrombin in vitro, thus resulting in generation of thrombin. Clotting factor X was converted to the active form (Xa) by both Candida and Pseudomonas proteinases, but not by Serratia proteinase. These results suggest that peripheral and systemic blood circulation may be impaired by activation of the blood clotting cascade by microbial infections, especially in septic patients, which would enhance disseminated intravascular coagulation and multi-organ failure.

Amino Acid Sequence↗
PubMed1990

Activation of kallikrein-kinin system in human plasma with purified serine protease from Dermatophagoides farinae.

An aqueous extract from a mite culture, of Dermatophagoides farinae, activated prekallikrein to kallikrein in normal plasma. Crude protein preparation, obtained by ammonium sulfate precipitation (95% saturation) from the extract, exhibited high activity (0.81 units/mg protein) towards a synthetic substrate of coagulation factor XIIa, Boc-Gln-Gly-Arg-MCA, and had also activity to form kallikrein in human plasma deficient in coagulation factor XII. Treatment of the protein preparation with phenylmethylsulfonyl fluoride (PMSF), an inhibitor of serine enzyme, gave rise to inactivation of both activities. Thus, the serine protease specific for Boc-Gln-Gly-Arg-MCA in mite cultures of D. farinae was purified by ammonium sulfate precipitation and chromatographies on p-aminobenzamidine-sepharose CL-4B, DEAE-Toyopearl 650M, Sephadex G-75 superfine and Sephacryl S-200. The purified protease was homogeneous electrophoretically, and its molecular weight was estimated to be 30,000. The optimum pH and temperature were around 7.5 and 50 degrees C, respectively. The specific activity was 36 units/mg protein at pH 7.4 and 37 degrees C. The activity was completely inhibited by PMSF. The serine protease had the activity to activate the kallikrein-kinin system in normal human plasma.

Animals↗
PubMed1976

Studies on the blood clotting and fibrinolytic system in the plasma from a sei (baleen) whale.

Blood clotting and fibrinolytic systems were studied in the plasma of a sei whale (Balaenoptera borealis). The sei whale belongs to the suborder baleen whales of the order Cetacea. Whale plasma had a greatly prolonged kaolin-activated partial thromboplastin time and was deficient in Hageman factor (factor XII), Fletcher factor (a plasma prekallikrein), and PTA (factor XI). All other clotting factor activities were present in amounts comparable to that of normal human plasma. Whale plasminogen was activated by human urokinase, but not by streptokinase. Whale plasma contained inhibitory activities against thrombin, activated Stuart factor, activated PTA, activated Fletcher factor, and plasmin.

Animals↗
PubMed1976

Procoagulant and platelet aggregating properties of antilymphocyte sera.

Ten anti-human lymphocyte sera in clinical use at six transplant centers and five anti-nonhuman lymphocyte sera were studied for their procoagulant and platelet-aggregating properties. This investigation was initiated following the observation of a clinical episode of renal artery thrombosis, associated with the use of one of the sera in a patient who had received a cadaveric renal transplant. The procoagulant from this serum shortened the clotting times of individual samples deficient, respectively, in factors XII, XI IX, X VIII, and VII. Esterolytic activity, demonstrated on the substrate benzoylarginine ethyl ester, was completely inhibited by phenylmethylsulfonyl fluoride, but coagulant activity was variably affected. The platelet-aggregating activity (PAA) has been identified as a complement-fixing gamma G antibody that was absorbed from the antilymphocyte serum (ALS) with human spleen lymphocytes. Five of the ten anti-human lymphocyte sera showed varying procoagulant activity (PCA), and six sera demonstrated PAA. Three sera contained both activities. The presence of both PCA and PAA in the same preparation may predispose patients to thrombotic events, particularly if administered intravenously. Sera should be screened for PCA and PAA prior to clinical use, and sera with these properties should be used with caution.

Animals↗
PubMedDate not supplied

Identification of proteins adsorbed from human plasma to glass bead columns: plasmin-induced degradation of adsorbed fibrinogen.

In a bead column experiment, attempts have been made to identify the proteins adsorbed from plasma onto a glass surface. Proteins adsorbed after a 3-h contact time were eluted sequentially by 1 M tris buffer and SDS. Polyacrylamide gel electrophoresis of eluted proteins showed a multiplicity of components, and not all of these could be identified. Positive identifications were made by immunodiffusion against specific antibodies, band positions on electrophoresis gels, and location of radioactivity in gels when specific radiolabeled proteins were added to plasma. Proteins found were albumin, IgG, fibrinogen, plasminogen, and fibrinogen degradation products (FDP). A major component with an apparent molecular weight of 25,000 remains unidentified. It is unrelated to albumin, IgG, fibrinogen, factor XII, or plasminogen. Adsorbed fibrinogen was less degraded when experiments were performed with plasmas deficient in either plasminogen or factor XII. It is therefore concluded that FDP are formed by activation of adsorbed plasminogen, as was found previously for purified fibrinogen containing a trace of plasminogen. At least part of this activation is potentiated by the contact activation phase of plasma coagulation, in particular activated factor XII.

Adsorption↗
PubMed2002

The in vitro analysis of the coagulation mechanism of activated factor VII using thrombelastogram.

We investigated the effects of addition of recombinant activated coagulation factor VII (rFVIIa) to coagulation factor-deficient plasma and whole blood, using thrombelastograms (TEGs). The addition of rFVIIa to factor II- or X-deficient plasma did not correct hemostatic parameters, whereas it produced partial responses in factor V-, VIII- or IX-deficient plasma and good responses in factor VII-, XI- or XII-deficient plasma. Furthermore, the addition of rFVIIa and platelets (30-100 x 10(3)/ micro l) to platelet-poor plasma produced marked corrections, producing TEGs similar to those of platelet-rich plasma. These results indicate that factors II and X are essential for the hemostatic effects of rFVIIa, and that factors V and VIII promote these effects. We believe that TEGs are, at present, one of the most useful tools for evaluating in vitro hemostatic effects of rFVIIa.

Adult↗
PubMed1991

Mechanized assay of plasma prekallikrein by activation with Pseudomonas aeruginosa elastase and amidolysis of chromogenic substrate.

An automated assay of plasma prekallikrein is described. Prekallikrein was converted to kallikrein with Pseudomonas aeruginosa elastase, and the hydrolytic activity of kallikrein to H-D-Pro-Phe-Arg-paranitroanilide subsequently measured. The conversion was complete within 8 minutes and the amidolytic activity remained stable at least another 10 min at 37 degrees C. This method worked in plasma deficient in Hageman factor (blood coagulation factor XII). Using anti-prekallikrein antibody and plasma deficient in prekallikrein, the amidolytic activity generated in normal plasma was identified as due to kallikrein. With plasma samples, the coefficients of variation (CV) for multiple measurements within run (n = 10) and between run (n = 10) were as low as 5.0% and 6.6%, respectively, and the minimum measurable concentration of prekallikrein in plasma was 10% of the normal level.

Adult↗
PubMed1979

Human high molecular weight kininogen. Studies of structure-function relationships and of proteolysis of the molecule occurring during contact activation of plasma.

Human high Mr kininogen was purified from normal plasma in 35% yield. The purified high Mr kininogen appeared homogeneous on polyacrylamide gels in the presence of sodium dodecyl sulfate and mercaptoethanol and gave a single protein band with an apparent Mr = 110,000. Using sedimentation equilibrium techniques, the observed Mr was 108,000 +/- 2,000. Human plasma kallikrein cleaves high Mr kininogen to liberate kinin and give a kinin-free, two-chain, disulfide-linked molecule containing a heavy chain of apparent Mr = 65,000 and a light chain of apparent Mr = 44,000. The light chain is histidine-rich and exhibits a high affinity for negatively charged materials. The isolated alkylated light chain quantitatively retains the procoagulant activity of the single-chain parent molecule. 125I-Human high Mr kininogen undergoes cleavage in plasma during contact activation initiated by addition of kaolin. This cleavage, which liberates kinin and gives a two-chain, disulfide-linked molecule, is dependent upon the presence of prekallikrein and Factor XII (Hageman factor) in plasma. Addition of purified plasma kallikrein to normal plasma or to plasmas deficient in prekallikrein or Factor XII in the presence or absence of kaolin results in cleavage of high Mr kininogen and kinin formation.

Amino Acids↗
PubMed1982

The contact activation mechanism in human plasma: activation induced by dextran sulfate.

Incubation of normal human plasma with dextran sulfate for 7 min at 4 degrees C generates kallikrein amidolytic activity. No kallikrein activity is generated in factor XII or prekallikrein-deficient plasma and only small amounts (8%) in high molecular weight (HMW) kininogen-deficient plasma. Addition of specific antisera directed against prekallikrein or HMW kininogen to normal plasma blocked the generation of kallikrein activity by dextran sulfate. Thus, factor XII, prekallikrein, and HMW kininogen are essential components for optimal activation of prekallikrein. The role of limited proteolysis in the activation of prekallikrein induced by dextran sulfate was studied by adding 125I-prekallikrein to plasma. The generation of kallikrein activity paralleled the proteolytic cleavage of prekallikrein as judged on SDS gels in the presence of reducing agents. The same cleavage fragments were observed as obtained by activation of purified prekallikrein by beta-factor-XIIa. Addition of 131I-HMW kininogen and 125I-factor XII or 131I-HMW kininogen and 125I-prekallikrein to normal plasma followed by activation with dextran sulfate and analysis on SDS gels indicated that the observed cleavage of prekallikrein and HMW kininogen is fast compared to the observed cleavage of factor XII, which is much slower and less extensive. During the first minutes of incubation of normal plasma with dextran sulfate, mainly alpha-factor-XIIa is formed. During prolonged incubation, beta-factor-XIIa is also formed.

Dextran Sulfate↗