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)

Activated Protein C (APC) resistance, one of the most common genetic risk factors for venous thrombosis, is caused by a single base mutation (G1691-->A) in the factor V (FV) gene resulting in the replacement of Arg506 by Gln at a predominant cleavage site for APC. Great progress in understanding the mechanism of downregulation of FVa activity via the protein C pathway has been achieved by studying APC-mediated inactivation of FVa purified from homozygous APC-resistant individuals. This review briefly summarizes the role of FVa in prothrombin activation and the structure-function relationship of FV and FVa. Subsequently, APC-dependent inactivation of FVa and FVa Leiden and its modulation by protein S and factor Xa in model systems containing purified proteins is discussed. FV also has a function in increasing the inactivation of FVIII/VIIIa by APC. This cofactor activity appears diminished in FV Leiden. Thus, an intricate mechanism of regulation of thrombin formation via the protein C pathway is starting to emerge. Extensive studies in plasma milieu will be needed to gain more insight into the relation between the presence of FV Leiden and impaired downregulation of thrombin formation in APC-resistant individuals.
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PMID:Regulation of thrombin formation by activated protein C: effect of the factor V Leiden mutation. 924 9

The prothrombinase complex (factor [F]Xa, FVa, calcium ions, and lipid membrane) converts prothrombin to thrombin (FIIa). To determine whether plasma lipoproteins could provide a physiologically relevant surface, we determined the rates of FIIa production by using purified human coagulation factors, and isolated fasting plasma lipoproteins from healthy donors. In the presence of 5 nmol/L FVa, 5 nmol/L FXa, and 1.4 micromol/L prothrombin, physiological levels of very low density lipoprotein (VLDL) (0.45 to 0.9 mmol/L triglyceride, or 100 to 200 micromol/L phospholipid) yielded rates of 2 to 8 nmol Flla x L(-1) x s(-1) in a donor-dependent manner. Low density lipoprotein (LDL) and high density lipoprotein (HDL) also supported prothrombinase but at much lower rates (< or =1.0 nmol FIIa x L(-1) x s[-1]). For comparison, VLDL at 2 mmol/L triglyceride yielded approximately 50% the activity of 2X10(8) thrombin-activated platelets per milliliter. Although the FIIa production rate was slower on VLDL than on synthetic phosphatidylcholine/phosphatidylsenne vesicles (approximately 50 nmol FIIa x L(-1) x s[-1]), the prothrombin Km values were similar, 0.8 and 0.5 micromol/L, respectively. Extracted VLDL lipids supported rates approaching those of phosphatidylcholine/phosphatidylserine vesicles, indicating the importance of the intact VLDL conformation. However, the presence of VLDL-associated, factor-specific inhibitors was ruled out by titration experiments, suggesting a key role for lipid organization. VLDL also supported FIIa generation in an assay system comprising 0.1 nmol/L FVIIa; 0.55 nmol/L tissue factor; physiological levels of FV, FVIII, FIX, and FX; and prothrombin (3 nmol/L FIIa x L(-1) x s[-1]). These results indicate that isolated human VLDL can support all the components of the extrinsic coagulation pathway, yielding physiologically relevant rates of thrombin generation in a donor-dependent manner. This support is dependent on the intact lipoprotein structure and does not appear to be regulated by specific VLDL-associated inhibitors. Further studies are needed to determine the extent of this activity in vivo.
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PMID:Plasma lipoproteins support prothrombinase and other procoagulant enzymatic complexes. 951 15

In 18 sportsmen the platelet count, thrombin time, prothrombin time, activated partial thromboplastin time (APTT), cloting factors (F):I, VII, VIII and fibrin/fibrinogen degradation products (FDP) were measured before, immediately after progressive incremental exercise--and 30 min later. All post-exercise changes of the values were corrected for the plasma volume changes, which were calculated from hematocrit values. Platelet count, thrombin time, prothrombin time FI and FVII did not change significantly after exercise. Immediately post-exercise APTT was significantly shortened, but FVIII and FDP were significantly elevated. 30 min later FDP level normalized but FVIII and APTT changes persisted. The obtained data show that the applied physical exercise caused shift of the existing balance between coagulation and fibrinolysis towards hypercoagulability. They also confirm the necessity of taking into account post-exercise hemostasis changes in cardiological rehabilitation and endurance training in adults.
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PMID:[The effect of progressive incremental exercise on some parameters of hemostasis]. 973 91

A case of acquired hemophilia A in a 65-year-old woman is presented. The patient had been subjected to cholecystectomy 2 months before the bleeding tendency appeared. On admission, she had easy bruising and prolonged activated partial thromboplastin time, but during hospitalization she had severe hemorrhage into the right gluteal and femoral muscles. An inhibitor of the factor VIII coagulant protein (FVIII:C) of high Bethesda titer was found in her serum. The patient was successfully treated with activated recombinant human factor VII (rhFVIIa) and immunosuppression. We conclude that rhFVIIa is a safe, effective, and fast-acting preparation for the treatment of severe hemorrhage in patients with acquired hemophilia A, and that the simultaneous administration of azathioprine and corticosteroids may suppress production of the inhibitor.
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PMID:Severe acquired hemophilia A successfully treated with activated recombinant human factor VII. 979 81

A high purity factor VIII/von Willebrand Factor (FVIII/vWF) concentrate (IMMUNATE [STIM plus]) (n = 6 batches), and a high purity factor IX (FIX) concentrate (IMMUNINE [STIM plus]) (n = 7 batches), were assessed in vitro for their applicability to continuous infusion. Parameters pertinent to continuous infusion were investigated and included stability, sterility and, in the case of FIX, the generation of potentially thrombogenic components. Four stationary or transportable mini infusion pumps, equipped with polyethylene, polypropylene or polyvinylchloride plastic components were used. The concentrates were reconstituted without extra filling volume and perfused at 12.5 mL h-1 and 1 mL h-1; sampling was carried out at the start of the experiment and for up to 48 h. The FVIII procoagulant activity (FVIII:C) was assayed by amidolytic, 1-stage and 2-stage assays; vWF was examined for ristocetin cofactor activity, antigen and multimers. The FIX coagulation activity (FIX:C) was determined by a 1-stage coagulation assay; thrombogenicity potential was assessed in vivo (Wessler stasis model in rabbits) and in vitro (FIXa and nonactivated thromboplastin time). Reconstituted concentrate incubated under the same conditions served as a control. Both concentrates remained sterile throughout the testing period. The perfused and control samples remained stable, retaining over 95% of activity for FVIII:C and over 90% for FIX:C for up to 48 h. Intermittent decrease of FVIII:C or FIX:C was not observed, suggesting no adsorption of FVIII or FIX onto plastic surfaces during either short or long-term exposure. No thrombogenic components were detected in the high purity FIX concentrate. Thus, under the in vitro conditions used, FVIII/vWF and FIX were found to be suitable for administration by continuous infusion.
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PMID:Continuous infusion of FVIII and FIX concentrates: in vitro analysis of clinically relevant parameters. 1021 43

Granulocyte colony-stimulating factor (G-CSF) is used in healthy donors of peripheral blood stem cells (PBSC) for allogeneic transplantation. However, some data have recently suggested that G-CSF may induce a hypercoagulable state, prompting us to study prospectively 22 PBSC donors before and after G-CSF 5 microg/kg twice daily. We sought evidence for changes in the following parameters: platelet count, von Willebrand factor antigen (vWF:Ag) and activity (vWF activity), beta-thromboglobulin (beta-TG), platelet factor 4 (PF-4), platelet activation markers (GMP-140 and PAC-1), activated partial thromboplastin time (aPTT), prothrombin time (PT), coagulant factor VIII (FVIII:C), thrombin-antithrombin complex (TAT), prothrombin fragment 1+2 (F1+2), thrombomodulin (TM) and tissue plasminogen activator antigen (tPA:Ag) prior to G-CSF and immediately before leukapheresis. ADP-induced platelet aggregation studies were also performed. G-CSF administration produced only mild discomfort. We found a significant increase in vWF:Ag (from 0.99 +/- 0.32 U/ml to 1.83 +/- 0.69 U/ml; P < 0.001), in vWF activity (from 1.04 +/- 0.34 U/ml to 1.78 +/- 0.50 U/ml; P < 0.001) and in FVIII:C (from 1.12 +/- 0.37 U/ml to 1.73 +/- 0.57 U/ml; P < 0.001) after G-CSF. Of note, four donors with low baseline vWF had a two- to three-fold increase after receiving G-CSF. G-CSF had no impact on the platelet count, beta-TG, PF-4, GMP-140 or PAC-1. The final% of platelet aggregation decreased from 73 +/- 22% to 37 +/- 26% after G-CSF (P < 0.001). We found a significant decrease in aPTT after G-CSF (29.9 +/- 3.1 s to 28.3 +/- 3.3 s; P = 0.004), but the PT was unaffected. In addition, we also observed a significant increase in TAT, F1+2 and TM, but not in tPA:Ag. Our data suggest that G-CSF may possibly induce a hypercoagulable state by increasing levels of FVIII:C and thrombin generation. In contrast to this information, we found reduced platelet aggregation after G-CSF administration. The clinical implications of these findings remain unclear and larger studies are definitely required.
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PMID:A prospective study of G-CSF effects on hemostasis in allogeneic blood stem cell donors. 1037 63

Prothrombin time (PT) and activated partial thromboplastin time (APTT), popularized as a routine assay for screening blood coagulation disorders and monitoring anticoagulant therapy, still involve some issues regarding standardization. In this lecture, we present propositions to resolve these problems in respective laboratory. Although international normalized ratio (INR) calculated by international sensitivity index (ISI) of PT reagent seems to improve discrepancy of sensitivity between reagents, local calibration of sensitivity of PT reagent in respective laboratories (local SI) is reasonable to make INR/ISI system more useful. However, local calibration of reagent is not easy by WHO recommended method in a small size laboratory. By using AK calibrant (IMMUNO AG), one of calibration plasma for INR, we investigated its possibility to calibrate local SI in four different reagents, compared with the recommended methodology. The results led the following process to determine reagent and calibrate local SI for practical use of INR/ISI system. (a) Use PT reagent of which ISI is close to 1.0 if possible, and utilize manufacture's ISI as is for INR. (b) Select PT reagent labeled specific ISI for an instrument as the same as used in the lab., and use the manufacture's ISI as is, if impossible to choose small ISI reagent. (c) If use a reagent of which ISI is close to 2.0 and shown no specific ISI for used detector, adjustment of local SI by commercial calibration plasma is recommended when unavailable warfarinized patient plasma. In APTT, we attempted to evaluate sensitivity between five different APTT reagents with a patient model by hemophilia A plasma contained various FVIII: C. This model reflected difference of sensitivity between reagents in results. Because standardization of APTT is not improved in this point, certification of APTT pattern in each laboratories with patient models is required for not only monitoring of heparinization, but also screening of typical coagulation disorders such as hemophilia and von Willebrand disease.
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PMID:[Suggestions and propositions to resolve some issues for standardization of prothrombin time and activated partial thromboplastin time]. 1037 64

By virtue of a severely prolonged aPTT with a normal thromboplastin time (prothrombin time) and a normal thrombin time, severe FXII deficiency has been diagnosed in a woman without a bleeding diathesis or a history of thromboembolic complications. A deficiency of a factor of the contact activation system (FXII, prekallikrein, high molecular weight kininogen) is usually diagnosed during routine coagulation tests demonstrating a prolonged aPTT. The severe and partial deficiency of FXII, of prekallikrein or high molecular weight kininogen is not associated with a bleeding tendency. In contrast, severely factor XI deficient subjects may suffer from a mild hemorrhagic diathesis, whereas FVIII deficiency (hemophilia A, autoimmune "hemophilia", von Willebrand disease) and FIX deficiency (hemophilia B) are associated with a bleeding tendency of varying severity, depending on the clotting activity of FVIII or FIX, respectively. An isolated prolongation of the aPTT due to a lupus anticoagulant, however, is frequently associated with arterial and/or venous thrombosis. Therefore, in case of a prolongation of the aPTT, its cause has to be determined.
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PMID:[A patient with isolated prolongation of aPTT without hemorrhagic diathesis anamnesis: severe, hereditary factor XII deficiency]. 1051 21

Blood coagulation occurs efficiently on cell surfaces such as activated platelets and monocytes, and fibroblasts. It is initiated by limited amounts of tissue factor (TF) exposed at the sites of vascular injury that complexes with trace amounts of circulating factor VIIa (FVIIa). Additional FVIIa-TF complexes are formed from FVII-TF involving positive feedback loops, including FVIIa-TF as well as factors Xa and IXa as they are formed in subsequent steps. For sustained normal coagulation to proceed, effective in vivo activation of factor X requires the participation of factor IXa generated via the FVIIa-TF complex. This may, in part, be due to effective inhibition of factor Xa and FVIIa-TF complex by tissue factor pathway inhibitor that results in blockage of direct activation of factor X by the FVIIa-TF complex. Additional generation of factor Xa at injury sites may then proceed via the FIXa-VIIIa pathway. Thrombin generated from prothrombin via complex formation of prothrombin with FXa and FVa on phospholipid surfaces (prothrombinase complex) powerfully accelerates coagulation by activation of FVIII and FV, and sustains coagulation through activation of FXI. Thus, in light of our current understanding of how blood clots in vivo, it is clear that both prothrombin time (PT) and activated partial thromboplastin time (APTT) are highly artificial in vitro systems with major limitations. Nevertheless, these tests are quite useful as global screening tests for abnormalities in the intrinsic or extrinsic, as well as common, pathways of coagulation and for monitoring of anticoagulant therapy.
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PMID:New insights into how blood clots: implications for the use of APTT and PT as coagulation screening tests and in monitoring of anticoagulant therapy. 1054 73

The influence of age on training-induced changes in resting and stimulated hemostatic potential was studied in three age categories (Cat I-III; 20-30 yr, 35-45 yr, and 50-60 yr, respectively) of sedentary men before and after 12 wk of training. Coagulation, fibrinolytic activity, and activation markers (reflecting fibrin formation and degradation) were determined. Physical conditioning resulted in a more pronounced increase in von Willebrand factor (vWF) and factor VIII clotting activity (FVIII:c) in Cat I and II and a more pronounced shortening of the activated partial thromboplastin time in all categories at maximal exertion and during recovery. Enhanced increases in tissue-type plasminogen activator (t-PA) antigen and activity and single-chain (sc) urokinase-type plasminogen activator (u-PA) at maximal exercise and 5 min of recovery were observed in all age groups after training. The effects on FVIII:c, vWF, and scu-PA were most pronounced in the youngest age group (Cat I). Increases in the marker of thrombin generation were highest in Cat III; no effect was seen on thrombin-antithrombin complex, plasmin-antiplasmin complex, and D-dimer in any of the age groups. We concluded that training enhances both coagulation and fibrinolytic potential during strenuous exercise. The effect on FVIII/vWF and t-PA/u-PA is most pronounced in younger individuals, whereas thrombin formation is most pronounced in older individuals.
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PMID:Aging, physical conditioning, and exercise-induced changes in hemostatic factors and reaction products. 1079 12


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