THE DIAGNOSIS AND MANAGEMENT OF BLEEDING DISORDERS.
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Anticoagulants↗
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Amidolytic assay of human factor XI in plasma: comparison with a coagulant assay and a new rapid radioimmunoassay.
The traditional coagulant assay for plasma factor XI suffers from a relatively high coefficient of variation, the need for rare congenitally deficient plasma, and a poor correlation between precision and sensitivity. We have developed a simple functional amidolytic assay for factor XI in plasma using the chromogenic substrate PyrGlu-Pro-Arg-p-nitroanilide (S-2366). After inactivation of alpha 1-antitrypsin, CI inhibitor, and other plasma protease inhibitors with CHCI3, plasma was incubated with kaolin, in the absence of added calcium, which limited the enzymes formed to those dependent on contact activation. Soybean trypsin inhibitor was used to minimize the action of kallikrein on the substrate. Once the reaction was complete, corn trypsin inhibitor was used to inactive factor XIIa, the enzyme generated by exposure of plasma to negatively charged surfaces, which had activated the factor XI. The assay is highly specific for factor XI, since plasma totally deficient in that zymogen yielded only 1%-3% of the enzymatic activity in normal plasma under identical conditions. The requirements for complete conversion of factor XI to XIa in plasma within 60 min were, respectively, factor XII, 0.6 U/ml, and high molecular weight kininogen, 0.2 U/ml. Prekallikrein was not an absolute requirement for complete activation but did accelerate the reaction. The intraassay coefficient of variation was 3.4%, and the mean of 35 normal plasmas was 1.00 U +/- 0.24 SD. In addition, a new rapid radioimmunoassay was devised using staphylococcal protein A as the precipitating agent for a complex of factor XI antigen with monospecific rabbit antibody. The mean was 1.01 U +/- 0.30 SD. The correlation coefficients for amidolytic versus coagulant and amidolytic versus radioimmunoassay were r = 0.95 for the former and 0.96 for the latter. Thus, a simple, accurate amidolytic assay and a radioimmunoassay have been devised for measuring factor XI in plasma that correlate well with the coagulant activity of factor XI, as determined in our laboratory.
Animals↗
Comparison of a chromogenic prothrombin time with clotting prothrombin time in the assessment of clinical coagulation deficiencies.
A chromogenic prothrombin time (CPT) has been compared with the standard prothrombin time (PT) or activated partial thromboplastin time (aPTT) in evaluating the hemostatic abnormality in patients with specific clotting factor deficiencies or liver disease and in patients receiving anticoagulant or fibrinolytic therapy. As expected, the CPT was sensitive to deficiencies of Factors II, V, X, and VII but was unaffected by deficiencies of Factors XII, XI, IX, or VIII. Due to the presence of polybrene in the thromboplastin formulation, the CPT was insensitive to heparin concentrations below 1 unit/mL. However, the assay result prolonged progressively between 1 and 10 units of heparin/mL, indicating that the CPT can be used to assay heparin concentrations within this range. Among patients with liver disease or who were receiving warfarin or fibrinolytic therapy, there was good correlation between the prolongation of the PT and the CPT. The results demonstrate that the CPT was sensitive to the commonly encountered clinical abnormalities in which the PT is prolonged and could be applied for monitoring oral anti-coagulant therapy. However, prolongation of the PT to a given value in different clinical conditions was associated with different degrees of prolongation of the CPT. This differential effect may reflect an abnormality in fibrinogen conversion to fibrin, which prolongs the PT but not the CPT and may also be contributed to by the differential sensitivity of the PT and CPT to specific factor deficiencies. The simplicity and reproducibility of the CPT warrant its further assessment, but correlation with the PT in a variety of clinical conditions is needed before clinical application can be undertaken.
Anticoagulants↗
Presence of factor-VII and -XIII activity in ultrafiltrate during hemofiltration.
UNLABELLED: Bleeding complications during renal replacement therapies can be attributed to coagulation system and platelet function alterations in uremia, and the application of heparin in extracorporeal circulation. Small protein losses during hemofiltration are always described, however the high molecular weight of coagulation factors should significantly prevent their removal during hemofiltration. To exclude degradation of coagulation factors under conditions of spontaneous ultrafiltration, the hemofiltrate of 40 patients with acute renal failure (treated with continuous veno-venous hemofiltration, CVVH) was sampled from the filtrate line after 1 h from the beginning of treatment and in 5 patients also after 12 and 24 h. Samples were investigated with human factor deficient plasma (VII, X, XI, XII) from donors with a congenital deficiency and with human plasma depleted of factor V, VIII, IX, and protein S and C. Factor XIII was detected photometrically. Subsequently the presence of factor- XIII and -VII activity was investigated in plasma and hemofiltrate from 16 patients treated with intermittent hemofiltration before (plasma) and after (plasma, hemofiltrate) therapy. These patients also suffered from acute renal failure and needed renal replacement therapies. Quality control was carried out with a buffer solution (<1% activity in the assays according to recommended protocols). RESULTS: Factor-V, -VIII, -IX, -X, -XI, and -XII activity, and protein C and S could not be detected in the hemofiltrate from continuous hemofiltration. Factor-VII and -XIII activity was present in the hemofiltrate (mean activity in CVVH: 1.93% for factor VII and 6.9% for factor XIII, mean activity in intermittent hemofiltration: <1% for factor-VII and 7.3% for factor-XIII). Three were no significant differences (Student's t-test) in plasma activity before and after intermittent hemofiltration of factor VII (44 vs. 47%, p = 0.39) and factor XIII (44 vs. 52%, p = 0.24). The presence of factor-VII and -XIII activity in the hemofiltrate cannot influence plasma activities in intermittent hemofiltration. Rapid new synthesis and short half-life should neutralize these effects. Elimination of coagulation factor-XIII activity should be excluded by the next generation of highly permeable membranes and on-line hemodiafiltration.
Acute Kidney Injury↗
PTA (factor XI) levels and coagulation studies after plasma infusions in PTA-deficient patients.
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Blood Coagulation Factors↗
Isolation and properties of a capillary injury-related protease from lung lymph.
Lung microvascular injury induced in sheep by intravenous infusion of Escherichia coli endotoxin, oleic acid, or air emboli caused the appearance in lung lymph of high levels of a protease with trypsin-like activity. The enzyme was isolated as an apparently homogeneous protein from pooled samples of active lung lymph, after an almost 9000-fold purification by affinity chromatography on columns of Reactive Blue 2-agarose, aprotinin-agarose, and p-aminobenzamidine-agarose, and chromatography on a column of Sephadex G-100. A molecular weight of about 70,000 to 75,000 was determined from mobility in polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The pH optimum was between 7.3 and 7.6. The isolated enzyme was quite labile, rapidly losing activity at both 37 and 25 degrees C. Addition of albumin to enzyme solutions protected against inactivation. Inhibition by diisopropylfluorophosphate and phenylmethanesulfonyl fluoride indicated that the enzyme belongs to the class of serine proteases. The enzyme cleaved peptide bonds on the carboxyl side of arginine residues and showed a relatively high affinity toward peptides containing several basic amino acid residues. Bonds involving the carboxyl group of lysine were cleaved at a much slower rate. The enzyme showed no plasminogen activator activity and its substrate specificity was quite different from that of several proteases of the clotting cascade. Its appearance in lymph was not influenced by lymph clotting and the isolated enzyme was not capable of correcting the clotting defect of plasmas deficient in factors XII, XI, IX, VII, and X.
Animals↗
Isolation from human plasma of a plasminogen activator identical to urinary high molecular weight urokinase.
Two different plasmatic plasminogen activators (PA) can be demonstrated after sodium dodecyl sulfate polyacrylamide gel electrophoresis of plasma freshly collected from resting volunteers, followed by transfer of the gels onto plasminogen-rich fibrin-agarose plates. These two PA are also present in plasmas deficient in coagulation Factor XI, Factor XII, prekallikrein, or high molecular weight-kininogen. The slower-moving PA has an apparent 85,000 Mr and is immunologically unrelated to urokinase (UK). The faster moving PA was isolated by immunoadsorption of plasma on anti-UK IgG coupled to Sepharose 4B and appears to be identical to urinary high molecular weight-UK.
Endopeptidases↗
[Unsuspected prolonged activated partial thromboplastin time in emergency surgery. Diagnostic and therapeutic guide].
Systematic complementary testing for asymptomatic patients before surgery yields an unexpectedly high percentage of anomalous results. Such results rarely affect perioperative management of the patient but may lead to unnecessary delays, which are potentially of great importance in emergency surgery. A 55-year-old woman with a clinical diagnosis of acute appendicitis was seen to have a prolonged activated partial thromboplastin time (APTT) of 1.94 before surgery. The patient's history did not suggest a coagulation disorder was likely, and when mixing normal and problem plasma failed to correct the APTT, we suspected an unspecified circulating anticoagulant was present. Surgery was delayed no further and no measures were taken. No excessive bleeding occurred during surgery or postoperative recovery. The main possible diagnoses for a women with unforeseen prolonged APTT are the presence of an unspecified circulating anticoagulant, factor XI or factor XII deficiency, or factor VIII deficiency associated with von Willebrand disease. Focusing on detecting a coagulation disorder while taking a patient's history and performing a simple laboratory test (mixing normal and problem plasma) can be useful for orienting management in emergency surgery.
Blood Coagulation Disorders↗
Structural role of Gly(193) in serine proteases: investigations of a G555E (GLY193 in chymotrypsin) mutant of blood coagulation factor XI.
In serine proteases, Gly(193) is highly conserved with few exceptions. A patient with inherited deficiency of the coagulation serine protease factor XI (FXI) was reported to be homozygous for a Gly(555) --> Glu substitution. Gly(555) in FXI corresponds to Gly(193) in chymotrypsin, which is the numbering system used subsequently. To investigate the abnormality in FXI(G193E), we expressed and purified recombinant FXIa(G193E), activated it to FXIa(G193E), and compared its activity to wild type-activated FXI (FXIa(WT)). FXIa(G193E) activated FIX with approximately 300-fold reduced k(cat) and similar K(m), and hydrolyzed synthetic substrate with approximately 10-fold reduced K(m) and modestly reduced k(cat). Binding of antithrombin and the amyloid beta-precursor protein Kunitz domain inhibitor (APPI) to FXIa(G193E) was impaired approximately 8000- and approximately 100000-fold, respectively. FXIa(G193E) inhibition by diisopropyl fluoro-phosphate was approximately 30-fold slower and affinity for p-aminobenzamidine (S1 site probe) was 6-fold weaker than for FXIa(WT). The rate of carbamylation of NH(2)-Ile(16), which forms a salt bridge with Asp(194) in active serine proteases, was 4-fold faster for FXIa(G193E). These data indicate that the unoccupied active site of FXIa(G193E) is incompletely formed, and the amide N of Glu(193) may not point toward the oxyanion hole. Inclusion of saturating amounts of p-aminobenzamidine resulted in comparable rates of carbamylation for FXIa(WT) and FXIa(G193E), suggesting that the occupied active site has near normal conformation. Thus, binding of small synthetic substrates or inhibitors provides sufficient energy to allow the amide N of Glu(193) to point correctly toward the oxyanion hole. Homology modeling also indicates that the inability of FXIa(G193E) to bind antithrombin/APPI or activate FIX is caused, in part, by impaired accessibility of the S2' site because of a steric clash with Glu(193). Such arguments will apply to other serine proteases with substitutions of Gly(193) with a non-glycine residue.
Animals↗
The measurement of factor XI (Plasma thromboplastin antecedent). Diagnosis and therapy of the congenital deficiency state.
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Blood Coagulation Factors↗
Low molecular weight factor X activator from Cerastes vipera (Sahara sand viper) venom.
Fraction G from Cerastes vipera venom previously purified on Sephadex G100 was refractionated on DEAE-Sephadex A50 column. A factor X activator was obtained. It had a mol. wt of 12,500 and an isoelectric point of 4.4. It shortened the plasma recalcification time of normal plasma, and plasmas deficient in factors V, VII, VIII, IX, XI and XIII, while it had no effect on plasma deficient in factor X or factor II. It had a serine protease activity and a minimal plasmin activity. PMSF, leupeptin and iodoacetamide exerted a pronounced inhibitory effect on its serine protease activity. Polyantivenin could neutralize the coagulant activity of the activator.
Amino Acid Sequence↗
Isolation and characterization of bovine plasma prekallikrein (Fletcher factor).
Prekallikrein (Fletcher factor) has been purified from bovine plasma approximately 25 000-fold with an overall yield of 14%. Purification steps included ammonium sulfate fractionation and column chromatography on heparin-agarose, DEAE-Sephadex, CM-Sephadex, benzamidine-agarose, and arginine methyl ester-agarose. The purified protein was homogeneous as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and amino-terminal sequence analysis. Bovine plasma prekallikrein is a glycoprotein with a molecular weight of 82 000 as determined by sedimentation equilibrium centrifugation. It contains 12.9% carbohydrate, including 6.2% hexose, 4.5% N-acetylglucosamine, and 2.2% N-acetylneuraminic acid. Prekallikrein is a single polypeptide chain with an amino-terminal sequence of Gly-Cys-Leu-Thr-Gln-Leu-Tyr-His-Asn-Ile-Phe-Phe-Arg-Gly-Gly. This sequence is homologous to the amino-terminal sequence of human factor XI (plasma thromboplastin antecedent). Both prekallikrein and kallikrein require kaolin to correct Fletcher factor deficient plasma. Kallikrein, however, has a specific activity 3.5 times greater than prekallikrein. Prekallikrein does not correct plasma deficient in factor XII (Hageman factor), factor XI, or high molecular weight kininogen (Fitzgerald factor).
Amino Acid Sequence↗
Novel anticoagulant from salivary glands of Simulium vittatum (Diptera: Simuliidae) inhibits activity of coagulation factor V.
Anticoagulant activity was detected in fractions of a reversed phase-high-performance liquid chromatography (RP-HPLC) of salivary gland lysate from Simulium vittatum Zetterstedt. Using a plasma recalcification time assay, these fractions did not inhibit factor Xa or thrombin. HPLC-purified fractions showing the anticoagulant property were pooled and examined using the activated partial thromboplastin time test conducted on normal plasma and plasmas deficient in factors V, VIII, IX, XI, and XII. The anticoagulant prolonged the clotting time of all the plasmas, except plasma deficient in factor V. The detection of antifactor V activity, together with other anticoagulants reported from Simulium spp. indicates a feeding strategy that targets enzymes in the terminal portion of the coagulation cascade.
Animals↗
Hemostasis in children with dysbacteriosis in chronic constipation.
The purpose of the study was to investigate hemostasis in children with dysbacteriosis disturbance in chronic constipation. The disturbance of factors in the inner mechanism of blood coagulation (VII, IX, XI, XII) in compensated chronic constipation was defined based on the reduction in colon bacillus levels. We observed hypocoagulation caused by the reduced activity of the prothrombin complex factors, disaggregate thrombocytopathy, and endotheliosis with fibrinolysis inhibition in subcompensated chronic colostasis with continuous reduction of colon bacillus levels and pathogenic microflora appearance. In decompensated colostasis there was an increase in pathogenic microorganisms and a continuous reduction of colon bacillus levels. In hemostasis there was a factor deficiency in inner (XII, XI, IX, VIII) and outer (II, V, VII, X) blood coagulation mechanisms. Fibrinolysis inhibition, endotheliosis development with thrombocyte aggregation, and microthrombosis formation were determined. Thus, in children with chronic constipation, there was a marked reduction in the amount of colon bacillus, which led to the reproduction of pathogenic bacteria. We also observed chronometric hypocoagulation with the inner (XII, XI, IX, VIII) and outer (II, V, VII, X) mechanisms of blood coagulation, at the base of which there is the deficiency of vitamin K-dependent factors (II, VII, IX, X) and a slightly marked disturbance in the final stage of coagulation. In thrombocyte vascular hemostasis, thrombocytopathy was observed with increased adenosine-5-diphosphate aggregation and the inhibition of the inner mechanism with fibrinolysis and endotheliosis.
Adolescent↗
Activation of human factor VII in plasma and in purified systems: roles of activated factor IX, kallikrein, and activated factor XII.
Factor VII can be activated, to a molecule giving shorter clotting times with tissue factor, by incubating plasma with kaolin or by clotting plasma. The mechanisms of activation differ. With kaolin, activated Factor XII (XII(a)) was the apparent principal activator. Thus, Factor VII was not activated in Factor XII-deficient plasma, was partially activated in prekallikrein and high-molecular weight kininogen (HMW kininogen)-deficient plasmas, but was activated in other deficient plasmas. After clotting, activated Factor IX (IX(a)) was the apparent principal activator. Thus, Factor VII was not activated in Factor XII-,HMW kininogen-, XI-, and IX-deficient plasmas, but was activated in Factor VIII-, X-, and V-deficient plasmas. In further studies, purified small-fragment Factor XII(a) (beta-XII(a)), kallikrein, and Factor IX(a) were added to partially purified Factor VII and to plasma. High concentrations of beta-XII(a) activated Factor VII in a purified system; much lower concentrations of beta-XII(a) activated Factor VII in normal plasma but not in prekallikrein or HWM kininogen-deficient plasmas. Kallikrein alone failed to activate partially purified Factor VII but did so when purified Factor IX was added. Kallikrein also activated Factor VII in normal, Factor XII-, and Factor IX-deficient plasmas. Purified Factor IX(a) activated partially purified Factor VII and had no additional indirect activating effect in the presence of plasma. These results demonstrate that both Factor XII(a) and Factor IX(a) directly activate human Factor VII, whereas kallikrein, through generation of Factor XII(a) and Factor IX(a), functions as an indirect activator of Factor VII.
Blood Coagulation↗
Current therapy for rare factor deficiencies.
Haemophilia A and B and von Willebrand disease account for 80-85% of all inherited bleeding disorders. The other 15% are represented by deficiencies of fibrinogen, prothrombin, or factors V, VII, X, XI, or XIII. In addition, acquired factor deficiencies are seen in a variety of conditions ranging from malignancies to autoimmune disorders. The spectrum of symptoms in these conditions varies from severe and life-threatening haemorrhage to a mild bleeding diathesis. The diagnosis depends on demonstration of decreased activity of one of the clotting factors. Due to the rarity of each of the individual factor deficiencies, purified factor concentrates are not as readily available as they are for haemophilia A and B. Treatment of rare clotting factor deficiencies consists of the most purified blood product available that contains the missing factor. Depending on which factor is deficient, either purified concentrates, prothrombin complex concentrates, cryoprecipitate, or fresh frozen plasma can be used. In addition, recombinant factor VIIa is available for treating factor VII deficient patients.
Blood Coagulation Factors↗
Human plasma kallikrein releases neutrophil elastase during blood coagulation.
Elastase is released from human neutrophils during the early events of blood coagulation. Human plasma kallikrein has been shown to stimulate neutrophil chemotaxis, aggregation, and oxygen consumption. Therefore, the ability of kallikrein to release neutrophil elastase was investigated. Neutrophils were isolated by dextran sedimentation, and elastase release was measured by both an enzyme-linked immunosorbent assay, and an enzymatic assay using t-butoxy-carbonyl-Ala-Ala-Pro-Val-amino methyl coumarin as the substrate. Kallikrein, 0.1-1.0 U/ml, (0.045-0.45 microM), was incubated with neutrophils that were preincubated with cytochalasin B (5 micrograms/ml). The release of elastase was found to be proportional to the kallikrein concentration. Kallikrein released a maximum of 34% of the total elastase content, as measured by solubilizing the neutrophils in the nonionic detergent Triton X-100. A series of experiments was carried out to determine if kallikrein was a major enzyme involved in neutrophil elastase release during blood coagulation. When 10 million neutrophils were incubated in 1 ml of normal plasma in the presence of 30 mM CaCl2 for 90 min, 2.75 micrograms of elastase was released. In contrast, neutrophils incubated in prekallikrein-deficient or Factor XII-deficient plasma released less than half of the elastase, as compared with normal plasma. The addition of purified prekallikrein to prekallikrein-deficient plasma restored neutrophil elastase release to normal levels. Moreover, release of elastase was enhanced in plasma deficient in C1-inhibitor, the major plasma inhibitor of kallikrein. This release was not dependent upon further steps in the coagulation pathway, or on C5a, since levels of elastase, released in Factor XI- or C5-deficient plasma, were similar to that in normal plasma, and an antibody to C5 failed to inhibit elastase release. These data suggest that kallikrein may be a major enzyme responsible for the release of elastase during blood coagulation.
Blood Coagulation↗
Variations of factor XII level during pregnancy in a woman with Hageman factor deficiency.
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Adult↗