[Congenital factor 13 deficiency: severe abdominal hemorrhage after combined antiinflammatory therapy].
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Appendectomy↗
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Demonstration of granulocytic proteases in plasma of patients with acute leukemia and septicemia with coagulation defects.
To show whether direct proteolysis of coagulation factors may play a role in patients with so-called consumption coagulopathy, granulocytic neutral proteases in the plasma of patients with acute myelocytic leukemia and septicemia were assayed by one- and two-dimensional Laurell electrophoresis. Complexes between serum alpha1-antitrypsin and elastase-like granulocytic protease could be demonstrated in those patients with acute myelocytic leukemia and septicemia who also had moderate or severe coagulation defects. Despite the presence of a high antiprotease potential, addition of the elastase-like enzyme to normal plasma resulted in coagulation defects in vitro comparable to those seen in the patients. These results and the ability of the elastase-like protease to destroy isolated clotting factors suggested that in certain types of coagulation factor deficiencies direct proteolysis rather than consumption of clotting factors due to disseminated intravascular coagulation may be operational.
Blood Coagulation Disorders↗
Isolation and functional properties of the heavy and light chains of human plasma kallikrein.
Human plasma kallikrein was prepared by proteolytic activation of prekallikrein with beta-Factor XIIa (Mr = 28,000). Two forms of kallikrein were generated that were each composed of two disulfide-linked polypeptide chains: a heavy chain of apparent Mr = 43,000 and a light chain of apparent Mr = either 36,000 or 33,000. Following reduction and alkylation, the heavy and light chains of kallikrein were isolated by affinity chromatography using insolubilized high molecular weight kininogen. The alkylated light chain of kallikrein did not bind to high molecular weight kininogen-Sepharose while the heavy chain did bind with high affinity and was subsequently eluted. The light chain retained the specific amidolytic activity of native kallikrein. The Km and kcat values for the hydrolysis of H-D-Pro-Phe-Arg-p-nitroanilide by kallikrein or its light chain were identical. Activation of Factor XII in solution was equally well catalyzed by kallikrein and its light chain. However, in kaolin-dependent coagulation, kallikrein was 180 times more effective than the light chain in correcting the clotting defect of prekallikrein-deficient plasma. Furthermore, the light chain was 3.5 times less potent than kallikrein in cleaving high molecular weight kininogen in solution. These observations indicate that the light chain region contains the enzymatic active site and adequately accounts for the enzymatic properties of kallikrein in solution on the protein substrate, Factor XIII, and on oligopeptide substrates. However, the heavy chain region of kallikrein is required for binding to high molecular weight kininogen, for surface-dependent activation of coagulation, and for optimal cleavage of high molecular weight kininogen.
Humans↗
Kaolin partial thromboplastin time: high levels of procoagulants producing short clotting times or masking deficiencies of other procoagulants or low concentrations of anticoagulants.
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Adolescent↗
Coagulation factor concentrate in the treatment of the haemorrhagic diathesis of fulminant hepatic failure.
To assess the value of clotting factor concentrate infusions in fulminant hepatic failure, a controlled trial was performed in which nine patients were randomly allocated to treatment with either concentrate alone or concentrate plus heparin. The five patients receiving concentrate alone all died, with major bleeding as the direct cause of death in three, whereas in the four receiving heparin as well there was only one instance of bleeding and one patient survived. Clinical evidence of intravascular coagulation appeared in two patients treated with concentrate alone and the laboratory evidence of this progressed during the period of infusions in all patients in both treatment groups, although to a lesser extent in those receiving heparin. Additional evidence for intravascular coagulation came from the changes observed in factor VIII levels which, although initially high in all patients, fell subsequently, particularly in those given concentrate alone. There was some improvement in the prothrombin ratio in both groups of patients but not complete correction, and serial assays of clotting factors showed that although factor II rose to high levels during treatment, factors IX and X showed little response. Thus, the use of concentrate of factor IX in this trial, as well as potentiating intravascular coagulation, was inadequate as replacement for the clotting factor deficiencies.
Acute Disease↗
Influence of factor XIIIa activity on human whole blood clot lysis in vitro.
We studied the influence of Factor XIIIa (F XIIIa) activity on the lysis rate of fresh whole human blood clots, without using anticoagulants. Clotting was induced by exogenous thrombin, lysis by tissue-type Plasminogen Activator (t-PA) added before clotting. After various periods of time, lysis rates were determined by measuring the radioactivity in the supernatant of the clot originating from 125I-Fibrinogen added before clotting. Lysis rates were determined in the presence of endogenous F XIIIa and compared with those obtained after specific inhibition of F XIIIa activity. We used an IgG fraction of an antiserum quenching the F XIIIa activity. Addition of increasing amounts of the antibodies to normal blood resulted in a dramatic increase in clot lysis rate, concomitant with loss of F XIII activity. Lysis of blood clots from a patient with a congenital, homozygous, functional alpha 2-Antiplasmin (alpha 2-AP) deficiency (alpha 2-AP-Enschede) was not or slightly increased by the anti F XIII antibodies indicating that fibrin-fibrin crosslinking per se does not contribute essentially to resistance of the blood clot against fibrinolysis. Both active alpha 2-AP and F XIIIa are required for the major part of the F XIII-dependent resistance of whole blood clots against lysis.
Antibodies↗
Life-threatening bleeding, pregnancy and lupus anticoagulant: success after steroid and anticoagulant therapy.
PROBLEM: The clinical manifestations associated with the presence of the lupus anticoagulant (LAC) are usually thrombotic and/or obstetric complications, specially miscarriages and/or repeated fetal deaths. The bleeding episodes in patients with LAC with no other coagulation disorders are exceptional, especially during pregnancy, intra- and postpartum. METHOD OF STUDY: Here we present two cases of patients with classification criteria of primary antiphospholipid antibody syndrome, a history of recurrent complicated pregnancies and massive bleeding during abortion and postpartum. We studied anticardiolipin (IgG/IgM), beta2glicoprotein-1 (IgG) and antimitochondrial (type 5) antibodies, LAC, rapid plasma reagin, coagulation test, clotting factors and, placental vascular flow from the second trimester of their last pregnancies. RESULTS: LAC was repeatedly detected in both cases. The prothrombin time and clotting factors including factors II and XIII were normal. Intrauterine growth restriction was also observed in both patients. Pre-eclampsia was detected in patient 2. We tried enoxaparin (60-80 mg/day) and prednisone (1 mg/kg/day) therapy and no maternal, hemorrhagic or thrombotic episodes were observed. CONCLUSIONS: Exceptionally, LAC may be associated with recurrent, life-threatening bleeding, even in patients with no prothrombin deficiency. The close follow-up and early anticoagulant and steroid therapy seems to be able to control thrombotic and hemorrhagic complications during the pregnancy and postpartum.
Adult↗
Rare coagulation deficiencies.
UNLABELLED: Deficiencies of coagulation factors (other than factor VIII and factor IX) that cause a bleeding disorder are inherited as autosomal recessive traits and are generally rare, with prevalences in the general population varying between 1 : 500 000 and 1 : 2 000 000. In the last few years, the number of patients with recessively transmitted coagulation deficiencies has increased in European countries with a high rate of immigration of Islamic populations, because in these populations, consanguineous marriages are frequent. Owing to the relative rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects and the actual management of bleeding episodes are not as well established as for haemophilia A and B. This article reviews these disorders in terms of their clinical manifestations and characterization of the molecular defects involved. The general principles of management are also discussed. KEYWORDS: afibrinogenaemia, autosomal recessive disorders, factor VIII, factor XI, factor XIII.
Blood Coagulation Factors↗
Release of alpha 2-plasmin inhibitor from plasma fibrin clots by activated coagulation factor XIII. Its effect on fibrinolysis.
When blood coagulation takes place in the presence of calcium ions, alpha 2-plasmin inhibitor (alpha 2PI) is cross-linked to fibrin by activated coagulation Factor XIII (XIIIa) and thereby contributes to the resistance of fibrin to fibrinolysis. It was previously shown that the cross-linking reaction is a reversible one, since the alpha 2PI-fibrinogen cross-linked complex could be dissociated. In the present study we have shown that the alpha 2PI-fibrin cross-linking reaction is also a reversible reaction and alpha 2PI which had been cross-linked to fibrin can be released from fibrin by disrupting the equilibrium, resulting in a decrease of its resistance to fibrinolysis. When the fibrin clot formed from normal plasma in the presence of calcium ions was suspended in alpha 2PI-deficient plasma of buffered saline, alpha 2PI was gradually released from fibrin on incubation. When alpha 2PI was present in the suspending milieu, the release was decreased inversely to the concentrations of alpha 2PI in the suspending milieu. The release was accelerated by supplementing XIIIa or the presence of a high concentration of the NH2-terminal 12-residue peptide of alpha 2PI (N-peptide) which is cross-linked to fibrin in exchange for the release of alpha 2PI. When the release of alpha 2PI from fibrin was accelerated by XIIIa or N-peptide, the fibrin became less resistant to the fibrinolytic process, resulting in an acceleration of fibrinolysis which was proportional to the degree of the release of alpha 2PI. These results suggest the possibility that alpha 2PI could be released from fibrin in vivo by disrupting the equilibrium of the alpha 2PI-fibrin cross-linking reaction, and that the release would result in accelerated thrombolysis.
Electrophoresis, Polyacrylamide Gel↗
[Diagnosis and treatment of coagulation disorders].
INTRODUCTION: Approximately 5% of all cerebrovascular events (CVE), and 10% of those occurring in young patients, are due to hematological disorders. Hypercoagulability states are related to CVE in young patients, deep vein thrombosis, recurrent thromboses, pulmonary embolism, a family history of thrombosis and unusual venous and arterial thromboses. DEVELOPMENT: The conditions related to increased risk of thrombosis are: the congenital thrombophilias due to deficiency of protein C, protein S or antithrombin III, resistance to protein C activated by Leiden's factor V--cofactor of protein C with genetic mutation--; the primary antiphospholipid syndrome with anticardiolipin antibodies and lupus inhibitor; platelet disorders, deficit of heparin cofactor II, deficit of plasminogen and plasminogen tissue activator (t-PA) and increase in the inhibitor of plasminogen tissue activator (PAI-I); alterations in factors of coagulation such as deficits of factor VII and factor XIII, mutation of prothrombin 20210-->A, increase in factor VIII. Hyperfibrinogenemia and hyperhomocysteinemia are also independent risk factors for CVE. CONCLUSION: The patients, especially young patients, with recurrent thrombosis or thrombosis of unknown origin should be assessed seeking clinical and serological signs of the primary antiphospholipid syndrome or other coagulopathies. Although we still have no results of controlled prospective studies regarding these conditions, long term anticoagulation is recommended on the findings of small-scale retrospective studies.
Anticoagulants↗
Coexisting dysfibrinogenemia (gammaR275C) and factor V Leiden deficiency associated with thromboembolic disease (fibrinogen Cedar Rapids).
Fibrinogen Cedar Rapids is a heterozygous dysfibrinogenemia (gammaR275C) that was associated with thromboembolism during and following pregnancy in three second-generation family members who also were heterozygotic for factor V Leiden (V R506Q). Like other dysfibrinogenemias with substitutions at position 275 of the gamma-chain, fibrinogen Cedar Rapids is characterized by defective end-to-end intermolecular fibrinogen and fibrin 'D : D' associations, a fibrin network structure that is composed of thicker and more highly branched fibers, normal fibrin 'D: E' associations, and normal factor XIII-mediated crosslinking of fibrinogen and fibrin. In addition, Cedar Rapids fibrinogen and fibrin displayed delayed plasmin lysis rates. Compared with normal fibrinogen, platelet aggregation or platelet fibrinogen receptor clustering was defective in the presence of fibrinogen Cedar Rapids. Most subjects with gammaR275 mutations do not experience clinical thrombotic disorders, suggesting that the combination of a factor V Leiden defect and a gammaR275C dysfibrinogenemia predisposes to thromboembolic disease.
Adult↗
Fibrinogen stabilizes placental-maternal attachment during embryonic development in the mouse.
In humans, maternal fibrinogen (Fg) is required to support pregnancies by maintaining hemostatic balance and stabilizing uteroplacental attachment at the fibrinoid layer found at the fetal-maternal junction. To examine relationships between low Fg levels and early fetal loss, a genetic model of afibrinogenemia was developed. Pregnant mice homozygous for a deletion of the Fg-gamma chain, which results in a total Fg deficiency state (FG(-/-)), aborted the fetuses at the equivalent gestational stage seen in humans. Results obtained from timed matings of FG(-/-) mice showed that vaginal bleeding was initiated as early as embryonic day (E)6 to 7, a critical stage for maternal-fetal vascular development. The condition of afibrinogenemia retarded embryo-placental development, and consistently led to abortion and maternal death at E9.75. Lack of Fg did not alter the extent or distribution pattern of other putative factors of embryo-placental attachment, including laminin, fibronectin, and Factor XIII, indicating that the presence of fibrin(ogen) is required to confer sufficient stability at the placental-decidual interface. The results of these studies demonstrate that maternal Fg plays a critical role in maintenance of pregnancy in mice, both by supporting proper development of fetal-maternal vascular communication and stabilization of embryo implantation.
Abortion, Spontaneous↗
[Evaluation of certain hemostasis parameters in premature infants].
In order to evaluate the specificity of hemostatic mechanism in premature Infants, the following examinations of coagulation and fibrinolytic parameters have been done: platelet number, concentrations of fibrinogen prothrombin, factors V, VII X, X, VIII, IX and XIII, antithrombin III, plasminogen, euglobulin lysis time, fibrin degradation products, alpha-1 antiplasmin and alpha-2 macroglobulin. The examinations have been done in the whole of 18 premature infants of both sexes. The obtained results show that lowered level of coagulant activity was not exclusively the consequence of low activity of vitamin-K dependent factors, but the result of more complex disorders partly connected with the transient reduction of factors VIII, XIII and fibrinogen. The total fibrinolytic activity, in the meantime, was of the normal intensivity. The established disorder of coagulation-fibrinolytic balance probably represents the certain contributing factor in more frequent occurrence of haemorrhagic syndrome in premature infants.
Antithrombins↗
[Disorders of hemostasis in liver cirrhosis. 2. Therapy].
Hemostatic changes in liver cirrhosis regularly have complex causes. In addition to a quantitative deficiency of hemostatic factors, also qualitative changes in coagulation factors, disturbances in coagulation factor metabolism and possible iatrogenic disturbances in plasmatic and thrombocytic hemostatic mechanism are to be considered. To diagnose a deficit of hemostatic factors is no problem, but to answer the question which of the numerous pathogenetic factors dominates in an individual case at this moment is very difficult and often impossible.
Antithrombin III↗
Factor XIII V34L polymorphism modulates the risk of chronic venous leg ulcer progression and extension.
Low Factor XIII (FXIII) activity has been reported in the blood of patients with chronic venous leg ulcer (CVU). In vivo studies have described increased wound healing in CVU patients treated with FXIII concentrate, and in vitro studies have shown increased regenerative capacity in FXIII-treated fibroblasts. In addition, a common G-to-T polymorphism in the FXIIIA-subunit gene (V34L) significantly increases the activity and modifies the cross-linking properties of the FXIII molecule and this variant has been investigated as a protective factor against thrombosis, a recognized risk factor for CVU establishment. Therefore, the role of FXIII levels, FXIII V34L, FVR506Q, and FIIG20210A, common gene polymorphisms in the pathogenesis of CVU was investigated. Ninety-one patients with CVU and 195 healthy controls (91 of them sex- and age-matched) were PCR-genotyped for the FXIIIV34L, FVR506Q, and FIIG20210A substitutions and FXIIIA-subunit levels were determined by immuno-electrophoresis. The extent of the venous ulcer surface in patients was measured by computer software. The allele frequency and the genotype distribution of the FXIII polymorphism did not show significant differences between the whole group of cases and controls as well as prothrombin variants did. On the contrary, the FVR506Q variant (FV Leiden) allele was more frequent in patients, yielding a significant OR value of 5.93 (95 percent CI, 1.83-19.17; p= 0.003). Considering only CVU cases secondary to a post-thrombotic syndrome (n= 24), FV Leiden yielded a greater OR value of 16.08 (95 percent CI, 4.33-59.6; p < 0.0001). When the CVU cases were stratified by the three possible FXIII genotypes, a significant trend toward a lower mean value of the ulcerated area was clearly evident as the number of the polymorphic alleles (L34) increased in the genotype of patients (VV = 11.9 cm(2,)+/- 23.6; VL = 6.1 cm(2,)+/- 6.9; LL = 4.1 cm(2,)+/- 2.8; p= 0.01). On the other hand, FXIIIA antigen levels were similar between CVU cases and matched controls, but 11 percent of cases had FXIII deficiency (FXIIIA </= 0.65 U/ml; p= 0.003) and they showed a greater mean extension of the lesion if compared with the remaining cases without FXIIIA deficiency (14.5 cm(2), +/- 20.2 vs. 9.0 cm(2), +/- 6.3; p= 0.08). We conclude that FXIII antigen levels and FXIII V34L polymorphism may play a crucial role in the complex cascade of CVU pathophysiology, being significantly related to the CVU progression and extension because of the direct effects they have on the FXIII molecular activity.
Aged↗
A method for preparation of fibrin glue.
Otorhinolaryngological operations would be facilitated by the use of a safe, cheap, surgical adhesive. Though commercial fibrin glue is effective, it is both relatively expensive and, because it is prepared from pooled human blood, there has been concern that it carries the risk of transmitting viral disease, in particular hepatitis and acquired immune deficiency syndrome. We describe a rapid, cheap method of preparing sufficient fibrin glue, of adequate bonding power, from a small quantity of the patient's own blood, and therefore with no risk of contracting viral disease. Our method of preparation of fibrin glue promises to provide a valuable adjunct to otorhinolaryngological surgical practice.
Aprotinin↗
A therapeutic, highly purified factor XI concentrate from human plasma.
A highly purified factor XI (FXI) concentrate was prepared from human plasma by a process comprising a filter adsorption step and chromatography on a cation exchange resin. The freeze-dried FXI, which solubilized quickly, had high specific activity (130-150 U/mg protein), high potency (approx. 100 U/mL), and excellent stability for at least 24 hours at room temperature in the liquid state. The overall recovery was about 220 U of FXI per liter of plasma. Minor protein contaminants (C1-inhibitor, fibronectin, IgG, and alpha-2-macroglobulin) were found to be between 0.13 and 0.46 mg per 1000 U of FXI. Fibrinogen and relevant coagulation factors (factors II, V, VII, IX, X, XII, XIII, and VIII/von Willebrand factor) were undetectable, as evidenced by immunologic and immunoelectrophoretic data. Components of the kinin system were present in trace amounts or were undetectable. No evidence of activated factors such as factors Xa and IXa was found. Proteolytic activity, as assessed by S-2288 chromogenic substrate, was negligible and thrombin was undetectable. A solvent-detergent treatment was included prior to chromatographic purification to enhance viral safety against lipid-enveloped viruses. In vitro and in vivo animal studies demonstrated the absence of thrombogenic, hypotensive, or toxic effects. No thrombogenic activity was found in the Wessler model in rabbits at doses of 900 to 1100 U of FXI per kg of body weight. This FXI preparation could be beneficial in substitution therapy of congenital or acquired FXI deficiency, especially as a way to avoid the use of fresh-frozen plasma.
Animals↗
Diagnostic and genetic studies on fibrin-stabilizing factor with a new assay based on amine incorporation.
Fibrinoligase, the fibrin cross-linking enzyme, transiently appearing during the course of coagulation in normal blood, was shown to catalyze the incorporation of a fluorescent amine, monodansylcadaverine [or N-(5-aminopentyl)-5-dimethylamino-1-naphthalene-sulfonamide] into casein. The reaction provided the basis of a sensitive fluorimetric method for measuring the activity of the enzyme (and also of similar other transpeptidases, such as transglutaminase). In tests involving plasma, certain difficulties had to be overcome which were mainly due to the fact that the enzyme itself does not occur in citrated plasma. Only its precursor (fibrin-stabilizing factor or factor XIII) is present, still requiring limited proteolytic activation by thrombin. Thus, in order to measure amine incorporation with plasma as a source of the factor, thrombin must be added. This necessitated a differential desensitization of the intrinsic fibrinogen so that the latter could not clot and could not thereby interfere with amine incorporation. Also, the thrombin-inactivating capacity of plasma had to be saturated to enable full conversion of the factor to the transpeptidase. Concentrations of casein, monodansylcadaverine, calcium, and hydrogen ions were chosen to permit almost maximal velocity of amine incorporation. A linear relationship with regard to plasma concentration could be obtained only under such conditions. No similar assay is presently available for quantitatively evaluating fibrin-stabilizing factor levels in plasma.The amine incorporation test was applied to a clinical case of hereditary total fibrin-stabilizing factor deficiency. The effect of transfusion therapy was studied, and some of the patient's relatives were examined. Whereas a paternal aunt and uncle gave values well within the normal range, a brother and the mother proved to be partially deficient and could be considered as heterozygous carriers. The father appeared to have a reduced level of fibrin-stabilizing factor, though not quite as low as the other two relatives. Two infusions (1 liter each) of fresh normal plasma, administered about 26 hr apart, brought levels in the patient's plasma close to those found in the mother and brother. The corrective power of the transfusions, however, rapidly declined within 5-6 days. Futility of the last transfusion could be ascribed to the appearance of a neutralizing antibody directed against the precursor stabilizing factor, a serious complication. General diagnostic versatility and potential of the quantitative amine incorporation assay with plasma is discussed.
Adult↗