[Hageman factor deficiency: second case found in Japanese].
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Blood Coagulation Disorders↗
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[INDICATIONS FOR FRESH BLOOD AND PRESERVED BLOOD IN DEFICIENCIES OF BLOOD COAGULATION FACTORS].
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Afibrinogenemia↗
Enzyme-linked coagulation assay. II. A sensitive assay for tissue factor and factors II, VII, and X.
We have developed a solid-phase clotting assay which uses peroxidase-fibrinogen in solution and fibrinogen bound to microtiter plates as a substrate for the thrombin generated from the clotting cascade. We have developed this assay for measurement of the extrinsic pathway factors thromboplastin (tissue factor, factor III), VII and VIIa, X, and II. Using long incubation times (40-90 min), thromboplastin could be measured in extracts of human brain at very low concentrations. Specificity for thromboplastin was demonstrated by showing a requirement for factors II, V, X, and VII but not for VIII, IX, XI, or XII; both substrate plasmas monodeficient in single factors and mixtures of the pure factors were used in demonstrating this specificity. The assay was modified to measure factors II, VII, VIIa, and X using appropriate deficient plasmas. The limit of detection was 2-3 orders of magnitude lower than a one-stage clotting test for all factors assayed. This assay has the advantages of convenience, specificity comparable to standard clotting tests, and high sensitivity.
Blood Coagulation Factors↗
A clinical evaluation of automated chromogenic tests as substitutes for conventional prothrombin time and activated partial thromboplastin time tests.
Automated procedures involving a chromogenic substrate sensitive to thrombin-sarcosine-Pro-Arg p-nitroanilide were compared with conventional tests for prothrombin times and activated partial thromboplastin times (APTT) and with specific assays for factors V, VII, VIII, IX, X, XI, and XII. The reproducibility and sensitivity of the chromogenic tests were compared with those of the clotting tests. Further, we have confirmed that the chromogenic test for APTT is sensitive to factor VII deficiency, unlike the clotting test for APTT. This might be an advantage in monitoring orally anticoagulated patients. The ready availability of the automated equipment for performing the chromogenic tests suggests their potential for routine use. However, some discrepant results in certain patients with liver disease and in others with factor VIII inhibitors warrant caution.
Autoanalysis↗
Reduced factor XII levels in patients with the antiphospholipid syndrome are associated with antibodies to factor XII.
Antibodies to factor XII (FXII) have previously been identified in some patients who were lupus anti-coagulant-positive. The relationship between these antibodies and FXII levels appeared to be variable. The aim of the present study was to confirm the presence of antibodies to FXII in patients with well characterized antiphospholipid syndrome (APS) and to establish their potential effect on levels of FXII. Forty-two patients with APS were studied; 21 patients were found to have either immunoglobulin (Ig)G or IgM antibodies to FXII by enzyme-linked immunosorbent assay (ELISA) using a highly purified preparation of FXII (> 99% pure). Levels of FXII were statistically significantly lower (P = 0.02) in patients with antibodies to FXII when compared with patients without antibodies to FXII (median = 91 micro/dl, s.d. = 39.1, median = 122 micro/dl, s.d. = 41.1 respectively). Four of the 21 patients with antibodies to FXII were found to have FXII levels below the laboratory normal range. Antibodies to FXII are present in significant numbers of patients with APS and may lead to acquired FXII deficiency.
Adult↗
Cerebral venous sinus thrombosis in infancy and childhood: role of genetic and acquired risk factors of thrombophilia.
UNLABELLED: Over a 3 year period the R506Q mutation in the factor V (FV) FV:Q506 gene, FV, factor XII (FXII), prothrombin, protein C, protein S, antithrombin, heparin cofactor II, anticardiolipin antibodies and lipoprotein (a) (Lp(a)) were measured in 32 infants and children with sinus thrombosis. Heterozygous FV:Q506 (n=5), homozygous FV:Q506 (n=2), homozygous FXII deficiency (n=1), protein C deficiency type I (n=5), protein C deficiency type II (n=1), antithrombin deficiency type I (n=1) increased Lp (a) (n=5), activated protein C-resistance without mutation in the FV gene (n=2), and increased anticardiolipin IgG antibodies (n=2) were diagnosed in the children investigated. In a further two patients we found combinations of increased Lp(a) with moderate hyperhomocystinaemia and heterozygous plasminogen deficiency with heterozygous FXII deficiency. In addition, increased anticardiolipin IgG antibodies were found in combination with heterozygous FV:Q506 (n=1) and protein C type I deficiency (n=2) respectively. Out of 32 patients with venous sinus thrombosis, 3 showed additional peripheral venous vascular occlusion. Contributing factors were present in 31 out of 32 patients investigated. Family members of 10 affected children had suffered from venous thrombo-embolism prior to the study. CONCLUSION: Our data suggest that additional contributing factors may promote manifestation of cerebral venous sinus thrombosis in infants and children with an inherited prothrombotic state. Further prospective studies are required to evaluate their potential role as "triggering" agents.
Child↗
A quantitative dot immunobinding assay for coagulation factor XII in plasma.
A dot immunobinding assay on nitrocellulose (NC) membranes has been developed for the quantification of human coagulation factor XII (F XII). Plasma samples were dotted on to NC filters and F XII was detected using a polyclonal antiserum followed by a radiolabelled antigen overlay. Dilutions of either pooled normal human plasma (NHP) or purified F XII in F XII deficient plasma were used as standards. Quantification was performed by measuring the radioactivity of bound 125I-F XII. Precise measurements of F XII antigen (F XII: Ag) were possible with a sensitivity down to 0.12 ng. Thus, dotting samples containing 0.5 microliter of plasma permitted detection of a F XII concentration corresponding to 1% of the level in NHP. The intra-assay coefficient of variation (CV) was less than 5% and the interassay CV was less than 16%. F XII:Ag in plasma samples of 50 healthy adults ranged from 12 micrograms/ml to 47 micrograms/ml. A good correlation (r = 0.93) existed between F XII:Ag and F XII clot promoting activity (F XII:C) in these samples. NHP contained 24.1 micrograms/ml F XII:Ag confirming earlier results obtained by other methods. In 16 pregnant women levels of F XII:Ag as well as of F XII:C were elevated, but F XII:Ag was disproportionately higher compared with F XII:C. The immunobinding assay has the following advantages: (1) rapid quantification of large numbers of samples is possible, (2) the sensitivity down to 1% of NHP is better than that of several other methods, (3) only very small amounts of both test material and reagents are needed.
Collodion↗
Activation of Hageman factor (factor XII) by bismuth subgallate, a hemostatic agent.
Bismuth subgallate is an effective agent in preventing hemorrhage after adenotonsillectomy. The experiments described demonstrate that this may occur through the activation of Hageman factor by this agent. Bismuth subgallate shortened the clotting time of whole blood, an action localized to an effect on the early steps of the intrinsic pathway; bismuth subgallate did not accelerate the thrombin time or prothrombin time of normal plasma, but could be substituted for kaolin as an activator of coagulation in assays of the partial thromboplastin time. The action of bismuth subgallate was localized to an effect on Hageman factor. It did not induce coagulation of plasma samples deficient in any of the recognized factors participating in the intrinsic pathway of thrombin formation, but it shortened the clotting time of plasma deficient in factor VII, a component of the extrinsic pathway. Evidence was obtained that Hageman factor exposed to bismuth subgallate corrected the defect of Hageman factor-deficient plasma and acquired amidolytic properties in the absence of other clotting factors. These studies provide a rationale for the hemostatic properties of bismuth subgallate.
Adolescent↗
Factor XII-independent activation of factor XI in plasma: effects of sulfatides on tissue factor-induced coagulation.
Factor XI (FXI) may be activated in a purified system by thrombin and by autoactivation in the presence of negatively charged substances such as dextran sulfate or sulfatides. The current studies were performed to determine if these processes occur during the coagulation of plasma. FXII--deficient plasma was supplemented with 125I-FXI and clot formation was induced with tissue factor and/or sulfatides. Cleavage of FXI was studied by standard polyacrylamide gel electrophoresis and autoradiography. Activated FXI (FXIa) was detected after 20 minutes of incubation with sulfatides alone and this process was markedly accelerated by the addition of tissue factor (TF). The enhancing effect of TF was blocked by hirudin, which indicated thrombin involvement in FXI activation. The contribution of FXIa to FIX activation in this system was studied using a 3H-FIX activation peptide release assay. Sulfatides increased FIX activation about twofold in plasma induced to clot with TF but had no effect if the plasma was immunodepleted of FXI. FIX activation was also increased in plasma induced to clot with FXa if sulfatides were present. The enhanced generation of FIXa was dependent on FXI and was blocked by hirudin. Some activation was seen in the reactions with sulfatides and hirudin and is likely solely caused by FXI autoactivation. The data indicate that during the coagulation of plasma in the presence of sulfatides, FXI is activated by a mechanism that is thrombin dependent and does not require FXII.
Blood Coagulation↗
The Fletcher factor-prekallikrein deficiency: a diagnostic test which identifies heterozygotes.
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Aminocaproates↗
Clinical importance of prothrombotic risk factors in pediatric patients with malignancy--impact of central venous lines.
UNLABELLED: To evaluate the role of inherited thrombophilia in the development of central venous line (CVL)-related thrombosis, the following parameters were determined in 77 pediatric-oncologic patients with CVL: activated protein C (APC)-ratio, factor V (FV) G1691A and prothrombin G20210A mutation, protein C, protein S, antithrombin, coagulation factor XII, lipoprotein (a) and homocysteine. An inherited prothrombotic risk factor was found in 17 patients (23%). Four out of 14 patients with a single detect (hyperlipoproteinemia, heterozygous FV G1691A and prothrombin G20210A mutation, protein C deficiency type I) and all three patients with combined defects (heterozygous FV G1691A mutation combined with heterozygous prothrombin G20210A variant, protein S deficiency or hyperlipoproteinemia) suffered from CVL-related thrombosis. In 11 out of 77 patients (14%) a CVL-related thrombosis was detected. In 2 children thrombosis occurred a few days after asparaginase therapy and in another three thrombosis was associated with CVL-related septicemia caused by Staphylococcus epidermidis. After removal of CVL, thrombosis was detected in 5 children, in 2 without clinical symptoms but in the presence of inherited prothrombotic risk factors. CONCLUSION: The present study demonstrates the clinical importance of CVL in combination with inherited thrombophilia in the development of thrombosis in pediatric-oncologic patients. Before or shortly after insertion of CVL, patients should be tested for the presence of factor V G1691A mutation, prothrombin G20210A variant and increased lipoprotein (a) values.
Adolescent↗
Comparison of functional aspects of the coagulation cascade in human and sea turtle plasmas.
Functional hemostatic pathways are critical for the survival of all vertebrates and have been evolving for more than 400 million years. The overwhelming majority of studies of hemostasis in vertebrates have focused on mammals with very sparse attention paid to reptiles. There have been virtually no studies of the coagulation pathway in sea turtles whose ancestors date back to the Jurassic period. Sea turtles are often exposed to rapidly altered environmental conditions during diving periods. This may reduce their blood pH during prolonged hypoxic dives. This report demonstrates that five species of turtles possess only one branch of the mammalian coagulation pathway, the extrinsic pathway. Mixing studies of turtle plasmas with human factor-deficient plasmas indicate that the intrinsic pathway factors VIII and IX are present in turtle plasma. These two factors may play a significant role in supporting the extrinsic pathway by feedback loops. The intrinsic factors, XI and XII are not detected which would account for the inability of reagents to induce coagulation via the intrinsic pathway in vitro. The analysis of two turtle factors, factor II (prothrombin) and factor X, demonstrates that they are antigenically/functionally similar to the corresponding human factors. The turtle coagulation pathway responds differentially to both pH and temperature relative to each turtle species and relative to human samples. The coagulation time (prothrombin time) increases as the temperature decreases between 37 and 15 degrees C. The increased time follows a linear relationship, with similar slopes for loggerhead, Kemps ridley and hawksbill turtles as well as for human samples. Leatherback turtle samples show a dramatic nonlinear increased time below 23 degrees C, and green turtle sample responses were similar but less dramatic. All samples also showed increased prothrombin times as the pH decreased from 7.8 to 6.4, except for three turtle species. The prothrombin times decreased, to varying extents, in a linear fashion relative to reduced pH with the rate of change greatest in leatherbacks>green>>loggerhead turtles. All studies were conducted with reagents developed for human samples which would impact on the quantitative results with the turtle samples, but are not likely to alter the qualitative results. These comparative studies of the coagulation pathway in sea turtles and humans could enhance our knowledge of structure/function relationships and evolution of coagulation factors.
Animals↗
Activation of Hageman factor (factor XII) by sulfatides and other agents in the absence of plasma proteases.
Incubation of purified human HF (factor XII) with sulfatides, EA, kaolin, or glass resulted in the generation of amidolytic activity in the apparent absence of other enzymes. Sulfatides or EA rapidly and efficiently initiated intrinsic coagulation in normal plasma but, under the conditions tested, only trivially corrected the prolonged partial thromboplastin clotting times of plasma deficient in prekallikrein or HMWK. Preliminary incubation of HF with crude IgG directed against plasma kallikrein or SBTI did not influence the results. The presence of albumin greatly enhanced activation of the amidolytic properties of purified HF by EA, even when albumin had been lipid-extracted or treated with DFP or SBTI; albumin also increased activation of HF by sulfatides. Internal cleavage and minimal scission of the HF molecule accompanied the generation of amidolytic properties in mixtures of HF and sulfatides; cleavage was not blocked by SBTI. These experiments demonstrate that negatively charged substances can activate HF in absence of other enzymes and that this activation is accompanied by formation of a two-chain species of HF.
Aniline Compounds↗
Production and characterization of a murine monoclonal antibody against a heavy chain of Hageman factor (factor XII).
A murine hybridoma cell line that produces a monoclonal antibody to human Hageman factor (HF, factor XII) is described. The antibody (P 5-2-1) consists of mouse IgG2b heavy chains and lambda light chains, selectively neutralizes HF procoagulant activity, and prevents the proteolytic cleavage of HF during contact activation in plasma. When HF is exposed to P 5-2-1 before the absorption of HF to kaolin, HF procoagulant activity is markedly inhibited. In contrast, P 5-2-1 does not interfere with HF activity after the adsorption of HF to kaolin. P 5-2-1 does not inactivate the prekallikrein-activating activity of 28,000-mol wt HF fragments (HFf). P 5-2-1 binds exclusively to the 40,000-mol wt portion of a heavy chain of HF and inhibits the adsorption of HF to negatively charged surfaces. P 5-2-1 immobilized on Sepharose can be used to deplete HF from normal human plasma. This immunoaffinity-depleted plasma is indistinguishable from congenital HF-deficient plasma and can be used as the substrate for HF procoagulant activity assay.
Absorption↗
Molecular basis for protein S hereditary deficiency: genetic defects observed in 118 patients with type I and type IIa deficiencies. The French Network on Molecular Abnormalities Responsible for Protein C and Protein S Deficiencies.
Circulating protein S (PS) is partly bound to C4b-binding protein, and only free PS can act as a cofactor for protein C (PC), a natural anticoagulant. Two types of PS deficiencies are commonly observed in patients with unexplained thrombosis, and they are characterized by having both a low total PS level and a low free PS level (type I) or by having only a low free PS level (type IIa). To elucidate the genetic mechanisms responsible for these two plasma phenotypes, we screened 118 symptomatic patients with type I or type IIa PS deficiency for a PS gene coding sequence variation. A total of 34 mutations, 17 of which were novel, were identified in 65 propositi (70% in type I and 44% in type IIa). In type I deficiency, 29 different mutations were distributed throughout the coding sequence. In type IIa deficiency, five different missense mutations were clustered in exons XII and XIII, with a Ser 460 to Pro mutation accounting for most cases (82%). This points to a role of the domain encoded by exons XII and XIII in the distribution between bound and free PS. The Ser 460 to Pro mutation was associated with the factor V Arg 506 to Gin mutation or a PC gene mutation in about half the patients, suggesting a cooperative effect on clinical expression.
DNA Mutational Analysis↗
Thromboembolism in children.
Acquired and inherited prothrombotic risk factors increase the risk of thrombosis in children. This review is based on "milestone" pediatric reports and new literature data (January 2001-February 2002) on the presence of acquired and inherited prothrombotic risk factors, imaging methods, and treatment modalities in pediatric thromboembolism. After confirming clinically suspected thromboembolism with suitable imaging methods, pediatric patients should be screened for common gene mutations (factor V G1691A, prothrombin G20210A and MTHFR C677T genotypes), rare genetic deficiencies (protein C, protein S, antithrombin, and plasminogen), and new candidates for genetic thrombophilia causing elevated levels of lipoprotein(a), and homocysteine, and probable genetic risk factors (elevations in fibrinogen, factor IX, and factor VIIIC, and decreases in factor XII). Data interpretation is based on age-dependent reference ranges or the identification of causative gene mutations/polymorphisms with respect to individual ethnic backgrounds. Pediatric treatment protocols for acute thromboembolism, including thrombolytic and anticoagulant therapy, are mainly adapted from adult patient protocols.
Child↗
Factor XI dependent and independent activation of thrombin activatable fibrinolysis inhibitor (TAFI) in plasma associated with clot formation.
Thrombin Activatable Fibrinolysis Inhibitor (TAFI) also known as plasma procarboxypeptidase B is activated by relatively high concentrations of thrombin in a reaction stimulated by thrombomodulin. In plasma an intact factor XI-dependent feed back loop via the intrinsic pathway is necessary to generate sufficient thrombin for TAFI activation. This thrombin generation takes place after clot formation with consequent down-regulation of fibrinolysis. We developed a specific and sensitive assay for activated TAFI (TAFIa) and studied its factor XI-dependent generation during clot formation. In the absence of thrombomodulin, addition of 20 nM thrombin to normal plasma generated 5-10% of the amount of TAFIa generated by 20 nM thrombin in the presence of 8 nM thrombomodulin. Minimal activation of TAFI was detected in factor II deficient plasma when clotting was initiated by 20 nM thrombin. Addition of 320-640 nM of thrombin to factor II deficient plasma resulted in the same amount of TAFIa as in normal plasma, suggesting that approximately 50% of factor II has to be converted to thrombin for extensive activation of TAFI. A Mab that neutralizes activated factor XII had no effect on TAFI activation indicating that an intact contact system is not necessary for the activation of TAFI. The dependency of TAFI activation of factor XI was tested using a Mab that neutralizes activated factor XI. When plasmas from 13 healthy individuals were tested, this Mab reduced TAFI activation by 65% (range 35-89%). Our results indicate that activation of TAFI in serum after clot formation can be quantitated and that it takes place in both factor XI-dependent and factor XI-independent mechanisms.
Blood Coagulation↗
[Pathogenesis and laboratory diagnosis of venous thrombosis].
UNLABELLED: Due to the increasing number of elderly as well as chronically-ill patients, venous thrombosis assumes an increasing role as a typical complication of many courses of disease. Postoperatively, in patients without anticoagulation, fibrinogen tests show venous thrombosis in the lower extremities in up to 50% but not all were clinically relevant. Prophylactic treatment has markedly lowered the manifestation of deep venous thrombosis. Nevertheless, in current epidemiologic studies, the prevalence of thrombotic disease is three-fold higher (1:7,500) than that of bleeding diseases (1:20,000). PATHOGENESIS: Congenital deficiency or congenital dysfunction of inhibitors of activated clotting factors have provided insight into the functional principles of limited proteolysis. Unequivocal causes of recurrent thrombosis are deficiency or dysfunction of AT III, protein C, protein S or plasminogen (Figure 1). Dysfibrinogenemia, in about 10% of the patients, leads to a tendency to thrombosis. Unclarified remains the relevance of lowered values for factor XII, heparin-cofactor II (HC II) and histidine-rich glycoprotein (HRG) (Table 1). Congenital disorders usually manifest themselves in the early adulthood. For the clinical manifestation of venous thrombosis, imbalance between pro-coagulatory and inhibitor factors are of importance, therefore the compensatory capabilities of other protease inhibitors, for example, alpha-2-macroglobulin should be taken into consideration. In acquired lowering of hemostasis factors, the balance in the plasma protein cascade should be assessed (Figure 1).(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Coagulation Tests↗