Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A spectrophotometric method for the assay of human blood coagulation factor VIII in plasma is presented. The chromogenic assay for factor VIII:C in plasma is performed in 3 steps: activation of factor VIII by thrombin; activation of factor X in a mixture of factor X, factor IXa, phospholipids/Ca2+ and plasma containing activated factor VIII, and determination of the rate of factor Xa formation with the chromogenic substrate S2337. Within-assay variation was between 5 and 6.9% for factor VIII:C activities between 20 and 150%. Clotting and chromogenic factor VIII:C activities were compared in plasma of 50 normal healthy donors (coefficient of correlation r = 0.83).
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PMID:Spectrophotometric method for the assay of human blood coagulation factor VIII. 311 24

Patients with diabetes mellitus have higher levels of coagulation factor VIII than the non-diabetic population. This may be a result of poor metabolic control and could contribute to the development of microvascular complications. During ketoacidosis there are acute changes in plasma concentrations of coagulation factors, some of which may be mediated by the rise in vasopressin that occurs. We have investigated the effects of hyperglycaemia without ketosis on some aspects of haemostasis by manipulating blood glucose concentrations using a Biostator. After a 1h run-in period with the blood glucose at 5 mmol/l, the blood glucose was maintained at 5, 15 and 25 mmol/l and maintained for one hour at each level in six male patients with insulin-dependent diabetes. Insulin was infused at 0.25 mu/kg/min. Venous blood samples were taken at the beginning and end of each hour after the run-in period for assays of factor VIII coagulant activity (FVIII:C), von Willebrand factor antigen (vWF:Ag), ristocetin co-factor (FVIIIR:Co), activated partial thromboplastin time (APTT) and vasopressin (aVP). There was a slight, though statistically insignificant fall in median factor VIII:C concentration at each incremental level of increase in blood glucose. Values (at the beginning and end of each hour) were: 1.0 and 1.1 iu/ml at 5 mmol/l; 0.95 and 0.79 iu/ml at 15 mmol/l; and 0.74 and 0.84 iu/ml at 25 mmol. vWF:Ag and FVIIIR:Co were unchanged. Plasma aVP fell slightly from 1.1 to 0.5 pg/ml. The results indicate that high levels of FVIII seen in diabetes are not due to short-term increases in blood glucose and that acute hyperglycaemia does not promote pro-coagulant changes in blood.
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PMID:Effect of controlled hyperglycaemia on factor VIII concentrations in insulin dependent diabetes mellitus. 313 35

Factor VIII Leiden is a genetic variant of coagulation factor VIII which has been detected in the plasma of a patient with mild haemophilia A. In this patient's plasma factor VIII procoagulant antigen was in 5-fold excess over factor VIII procoagulant activity, indicating the presence of an abnormal factor VIII molecule. The variant factor VIII was isolated from the patient's plasma, and its functional properties were studied in a factor X-activating system consisting of purified components. The isolated factor VIII Leiden was normally activated by factor Xa and by thrombin, but the activity of the factor VIIIa was about 3% of normal. The defect of factor VIIIa Leiden was studied by comparison with normal factor VIIIa in kinetic experiments of factor Xa formation. The results support the hypothesis that factor VIIIa Leiden has a reduced affinity for phospholipid-bound factor IXa in the intrinsic factor X-activating complex.
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PMID:The functional defect of factor VIII Leiden, a genetic variant of coagulation factor VIII. 393 62

The factor VIII complex is a macromolecule with two distinct components. One is the coagulation factor VIII. The other, known as the Willebrand factor, is a polymer which probably acts as a carrier for serum factor VIII. Hereditary disorders can affect either of these two components. Hemophilia A is a coagulation disorders due to decreased factor VIII coagulant activity. Increase of partial activated thromboplastin time parallels disease severity. Hematomas and hemarthrosis in large joints are the main clinical features. In von Willebrand disease, mucocutaneous bleeding is the main symptom. Diagnosis is established by demonstrating disorders of primary hemostasis: prolonged bleeding time and decreased ristocetin-induced platelet aggregation. Two forms of von Willebrand disease have been described. In the quantitative form, decreased synthesis of von Willebrand factor is often responsible for severe clinical manifestations. The qualitative form probably results from defective polymerization of von Willebrand factor subunits. In both these forms, deficient primary hemostasis is a consequence of decreased platelet adhesion to the vascular wall. Clinical and biological features of hemophilia A and von Willebrand disease, as well as their management, are discussed.
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PMID:[The factor VIII complex: hemophilia A and von Willebrand disease]. 629 93

Previous studies showed that the random addition of supplemental albumin to a resuscitation regimen of blood, salt, and frozen plasma caused a significant (p = less than 0.05) fall in fibrinogen clotting activity (FC) and a rise in prothrombin times (PT) in seriously injured patients; the partial thromboplastin times (PTT) were insignificantly prolonged. Based upon these findings, frozen plasma samples, prospectively collected in 41 non-albumin patients and 35 albumin patients, were analyzed immunologically, in duplicate, for protein content of coagulation factor VIII (VIIIAg), prothrombin (IIAg), fibrinogen (FAg), antithrombin III (ATAg), and fibrin(ogen) split products (FSP). Supplemental albumin resuscitation was associated with a significant fall in FAg (83 +/- 9 versus 124 +/- 10 SE mg/dl), VIIIAg (97 +/- 13 versus 127 +/- 135 SE %), IIAg (54 +/- 3 versus 80 +/- 4 SE %), and ATAg (14 +/- 0.8 +/- 19 +/- 0.8 SE mg%) with no significant changes in FSP. FSP, however, were more than 20 micrograms/ml in 13 of 41 nonalbumin patients versus four of 35 albumin patients (X2 = 4.5, p less than 0.05). Reduced coagulation activity following albumin supplementation seems partly caused by a decrease of coagulation protein content; increased fibrinolysis in the albumin patients is not the cause. Decreased coagulation protein content parallels the fall in coagulation activity and the need for postresuscitation blood transfusions. The role of reduced coagulation synthesis in these changes needs further study.
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PMID:Altered coagulation protein content after albumin resuscitation. 680 24

The common unfractionated heparin preparations (UFH) accelerate inhibition of most of the enzymes in the coagulation cascade, while low-molecular mass heparin (LMMH) mainly accelerates inhibition of activated coagulation factor X (FXa). The present study addresses the question of whether LMMH may be a weaker anticoagulant than UFH when the two preparations are added to plasma with equal FXa inhibitory activities. Normal and coagulation factor VIII (FVIII)-deficient plasma was used. Thrombin generation was determined by assaying the formation of the thrombin-antithrombin complexes (TAT) and of fibrinopeptide A (FPA), two parameters that showed a strong positive correlation. At a heparin concentration of 0.5 or 1.0 FXa-inhibiting IU/ml, the formation of TAT and FPA was substantial and always much more increased with LMMH than with UFH. At 4.0 FXa-inhibiting IU/ml, no FPA was generated, but traces of thrombin were. In recalcified FVIII-deficient plasma (one of the batches containing FVIII antibodies), more TAT was formed with 0.1 FXa-inhibiting IU/ml LMMH than with UFH with the same FXa-inhibiting activity. It is concluded that LMMH is a weaker anticoagulant than UFH, partly because of a poor thrombin inhibition capacity which facilitates acceleration of coagulation by FVIII activation and partly because of a poor inhibition of enzymes preceding the prothrombinase stage, both mechanisms leading to increased enzymatic activity above the prothrombin stage. As judged from the higher degree of thrombin generation with LMMH than with UFH, there is no support for the assumption that LMMH is as good an antithrombotic agent as UFH is, without reducing the haemostatic capacity as much as UFH does.
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PMID:Coagulation inhibition capacities of low-molecular mass and unfractionated heparin, as determined by thrombin generation. 799 54

Cimex lectularius salivary gland homogenate delayed the recalcification time of human citrated plasma. Separation of the salivary gland homogenate by molecular sieving HPLC chromatography resulted in a single major peak of anticlotting activity with an apparent molecular mass of 17,000. The anticoagulant principle inhibited the activation of factor X to factor Xa in the tenase complex (FVIII, FIXa, FX, phospholipids, and calcium). However, it did not directly inhibit already activated factor Xa, suggesting that the anticlotting activity is not an anti-factor Xa. Additionally, this salivary gland anticoagulant further retarded the recalcification time of factor VIII- and factor IX-deficient plasmas, suggesting that the anticlotting principle is not directly inhibiting either the coagulation factor VIII or factor IXa. Altogether these data suggest that the anticlotting activity is an inhibitor of the activation of factor X to factor Xa in the tenase complex.
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PMID:A novel inhibitor of factor X activation from the salivary glands of the bed bug Cimex lectularius. 868 87

Individuals with hemophilia A require frequent infusion of preparations of coagulation factor VIII. The activity of factor VIII (FVIII) as a cofactor for factor IXa in the coagulation cascade is limited by its instability after activation by thrombin. Activation of FVIII occurs through proteolytic cleavage and generates an unstable FVIII heterotrimer that is subject to rapid dissociation of its subunits. In addition, further proteolytic cleavage by thrombin, factor Xa, factor IXa, and activated protein C can lead to inactivation. We have engineered and characterized a FVIII protein, IR8, that has enhanced in vitro stability of FVIII activity due to resistance to subunit dissociation and proteolytic inactivation. FVIII was genetically engineered by deletion of residues 794-1689 so that the A2 domain is covalently attached to the light chain. Missense mutations at thrombin and activated protein C inactivation cleavage sites provided resistance to proteolysis, resulting in a single-chain protein that has maximal activity after a single cleavage after arginine-372. The specific activity of partially purified protein produced in transfected COS-1 monkey cells was 5-fold higher than wild-type (WT) FVIII. Whereas WT FVIII was inactivated by thrombin after 10 min in vitro, IR8 still retained 38% of peak activity after 4 hr. Whereas binding of IR8 to von Willebrand factor (vWF) was reduced 10-fold compared with WT FVIII, in the presence of an anti-light chain antibody, ESH8, binding of IR8 to vWF increased 5-fold. These results demonstrate that residues 1690-2332 of FVIII are sufficient to support high-affinity vWF binding. Whereas ESH8 inhibited WT factor VIII activity, IR8 retained its activity in the presence of ESH8. We propose that resistance to A2 subunit dissociation abrogates inhibition by the ESH8 antibody. The stable FVIIIa described here provides the opportunity to study the activated form of this critical coagulation factor and demonstrates that proteins can be improved by rationale design through genetic engineering technology.
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PMID:Characterization of a genetically engineered inactivation-resistant coagulation factor VIIIa. 934 26

Bleeding is a major problem during early excision of burned skin. Therefore, 13 severely burned adult patients operated on during the first week after the trauma were studied. Blood loss was replaced with crystalloids, colloids and packed red cell concentrates (PRC). After ten infused PRCs, four fresh frozen plasma (FFP) units were given and thereafter one FFP unit with one PRC unit. Arterial blood samples were drawn before anaesthesia (SO), during operation after every four units of PRC transfusion (S1-4), 4 h postoperatively (S5) and on the first postoperative morning (S6). Prothrombin time (%) and activated partial thromboplastin time (s) were abnormal before operation (median values 67%, range 22-99% and 44 s, range 30-86 s, respectively). Prothrombin time decreased during operation and reached the critical level for normal haemostasis at S2. Thrombelastography showed decreased clot formation rate and impaired fibrin platelet interaction peri- and postoperatively. Fibrinogen and factor VIII activity were high preoperatively (median 6.1 g/l and 253%) and the critical values for normal haemostasis were not reached. Burned patients have a consumption coagulopathy which, in combination with haemodilution during operation, results in a clinically significant deficiency of coagulation factors II, VII and X, in spite of reactive elevation of coagulation factor VIII and fibrinogen.
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PMID:Haemostatic disturbances in burned patients during early excision and skin grafting. 960 15

Haemophilia A is usually a genetic deficiency of coagulation factor VIII (F VIII). The development of antibodies against F VIII is a well known and frequent complication in the treatment of haemophilia A. Rarely, a F VIII inhibitor arises spontaneously, causing a condition which is known as acquired haemophilia A. We describe a patient with acquired haemophilia A and pemphigus, who presented with spontaneous haematomas of the extremities. Laboratory tests showed an activated partial thromboplastin time (aPTT) of 71 s (normal: 26-36 s), a F VIII concentration of 9% (normal: 60-140%), and a F VIII inhibitor-activity of 7.5 Bethesda Units/ml (B.U./ml, normal: 0). The haematomas disappeared within a few days and the laboratory tests normalized within 6 weeks, after administration of a booster of oral corticosteroids. One and a half years after the corticosteroids were stopped, both the clinical and the laboratory course of the patient has been uneventful. As far as we know, the combination of acquired haemophilia A and pemphigus has been reported in the literature only three times before. The diagnosis acquired haemophilia A should be considered in a patient presenting with a newly arisen haemorrhagic diathesis.
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PMID:A patient with acquired haemophilia A and pemphigus. 965 58


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