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)

Acquired hemophilia is a life-threatening bleeding disorder by the development of autoantibody against factor VIII. The therapeutic approach relies on steroid, cyclophosphamide and/or cyclosporine. A 64-year-old man was referred to our hospital with extensive hematoma in both psoas muscles, severe anemia of 6.8 g/dl, prolonged activated partial thromboplastin time over 200 seconds, and factor VIII coagulation activity (FVIII: C) of 1.9%. A factor VIII inhibitor was detected at 118 Bethesda units (BU). The diagnosis of acquired hemophilia was made in the absence of a detectable cause. The inhibitor was IgG with a subclass of IgG4 and reacted with 72 kDa fragment of factor VIII light chain. Steroid pulse therapy following steroid treatment resulted in the resolution of acquired hemophila with marked and prolonged efficacy.
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PMID:[Effective immunosuppresive therapies including steroid pulse treatment for intramuscular hematoma in iliopsoas in acquired hemophilia]. 1820 14

Several factor (F) VIII products of different origin and structure are being used for haemophilia A treatment worldwide. The assessment of FVIII concentration in these products is done using activity assays, which are dependent upon the assay and its modifications. To evaluate FVIII products for potency and for FVIII concentration and specific activity, three activity-based assays [activated partial thromboplastin time (APTT), intrinsic FXase and synthetic coagulation proteome] and two immunoassays (ELISA and western blotting) were used in this study with albumin-free full-length recombinant (r) FVIII as a standard. In all activity assays, products A and B (both contain full-length rFVIII) at 1 U mL(-1) showed potency similar to that of the 0.7 nm (1 U mL(-1)) rFVIII standard. Product E (contains truncated rFVIII) was less potent in the APTT (83% of standard) and product C (contains plasma FVIII) was less potent in FXase assays (66%). The ELISA immunoassay revealed that the specific activity of FVIII proteins in products A-C and E varied over a wide range (3900-13 200 U mg(-1)) and was higher for most lots when compared with the standard (5000 U mg(-1)), whereas the specific activity of product D (contains plasma FVIII) was lower than expected (3200-4800 U mg(-1)). (i) FVIII potency estimated in different assays gives dissimilar results; (ii) the specific activity of FVIII in various FVIII products is different and inconsistent. Thus, the administration of an equal FVIII potency in units means the administration of different amounts of FVIII protein, which may partly explain apparent discrepancies in product performance.
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PMID:Potency and mass of factor VIII in FVIII products. 1869 75

Severe hemophilia A (HA) patients develop inhibitory alloantibodies to factor VIII:C and therefore require bypass agents that are scarce, expensive and may provoke secondary effects. Twenty-three severe HA patients who were high-responders to FVIII inhibitors were studied. FVIII:C activity in plasma was measured by one-stage activated partial thromboplastin time method, and the quantification of FVIII:C inhibitors was carried out by the Nijmegen-Bethesda method. Inhibition kinetics was assessed through serial plasma dilutions. FVIII:C activity was <1% in all patients. Kinetics behavior of the inhibitors was classified as type I in 14 patients, type II in four and an intermediate pattern that we named type III in one case. We were unable to apply the regression model to the remaining four of 23 patients in the study because of their low inhibitory titer (<3 Nijmegen-Bethesda units per ml). Seventy-eight percent of the patients with inhibitor type I did not respond to high doses of FVIII therapy, whereas 50% of patients with type II kinetics did (P = 0.5323). Generally, patients belonging to the same family had similar kinetics behavior as well as concordant treatment response. Although nonsignificant, our results suggest an association between kinetics behavior and treatment response that may be a valuable prognostic parameter for the management of these patients.
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PMID:Kinetics of factor VIII:C inhibitors and treatment response in severe hemophilia A patients. 1877 97

In order to analyze the clinical features and laboratory findings in patients with acquired hemophilia A, one case of acquired hemophilia A was studied, the medical history, clinical features, ultrasonography and laboratory examination including activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT) and FVIII:C, FIX:C, FXI:C, FXII:C ratio, as well as medical treatment were analyzed. The results showed 99.3 sec of APTT, 13 sec of PT, and 13.5 sec of TT, 2% of FVIII:C, 7% of FIX:C, 9% of FXI:C and 21% of FXII:C. The prolongation of APTT could not be completely corrected by mixing the patient plasma with an equal volume of normal fresh plasma; the APTT increased with prolongation of incubation time, when patient plasma was mixed with an equal volume of normal fresh plasma and incubated at 37 degrees C. The plasma FVIII:C, FIX:C, FXI:C and FXII:C levels in patient were 6%, 75%, 95% and 123% respectively, when patient's plasma was diluted by tenfold and mixed with an equal volume of non-diluted normal plasma. FVIII inhibitor in the patient's serum was at a level >32.0 Bethesda units/ml after acquired hemophilia was diagnosed, the patient was admitted to hospital and given orally prednisone and azathioprine therapy. One month later, clinical status of the patient were improved with 33.3 seconds of APTT, 128% of FVIII level and elimination of FVIII inhibitor. In conclusion, inquiring case history, analyzing imaging results, detecting level of APTT, performing dilution test and assaying titer of FVIII inhibitor can reduce misdiagnosis and wrong therapy for patients with acquired hemophilia A. The FVIII inhibitor can be eliminated and function of clotting can be recovered by using immunosuppressive therapy.
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PMID:[Clinical analysis and laboratory findings in a patient with acquired hemophilia A]. 1923 80

Global tests of platelet function are often used as screening tests during the laboratory investigation of individuals with suspected hemostatic defects. Because global tests of platelet function do not enable specific diagnosis of platelet disorders, they are normally performed as the first part of a two-step strategy that requires further testing with more specialized assays of platelet function to confirm or refute the diagnosis. The most commonly proposed rationale for testing global platelet function as a first-line investigation is that normal test results may exclude a diagnosis of platelet function disorder so that further specialized testing can be avoided. For this reason, global platelet function tests are usually initially performed at the same time as global assays of coagulation pathway function (prothrombin time and activated partial thromboplastin time, von Willebrand factor screening tests [VWF:Ag, VWF:RCo, and FVIII:C]) and measurement of platelet number. The most widely performed tests for screening platelet function disorders are currently the template bleeding time and the closure time within the Platelet Function Analyzer. These tests will therefore be considered in detail in this review, and we will discuss the limitations of these methods in screening individuals for platelet disorders.
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PMID:Screening tests of platelet function: update on their appropriate uses for diagnostic testing. 1940 88

An initial presentation of hematological malignancies associated with autoantibodies is not common, and there is only one documented case of multiple myeloma presenting with acquired FVIII inhibitor for multiple myeloma. In this paper, we describe a second case of multiple myeloma who presented with acquired FVIII inhibitor. A 43-year-old woman was referred to our hematology unit for anemia and an elevated erythrocyte sedimentation rate. Two months before her admission, she had undergone an operation at a local hospital because of ovarian cyst rupture complicated by severe postoperative bleeding. Because coagulation tests had revealed a prolonged partial thromboplastin time which could not be corrected by a mixing test and a decreased FVIII level, a diagnosis of acquired FVIII inhibitor had been made. The patient was hospitalized in our unit for further evaluation. The erythrocyte sedimentation rate was 110 mm/h, serum albumin level 2.5 g/dL, globulin level 5.6 g/dL, and C-reactive protein 47.8 mg/L (0-6). Serum IgG was high, and serum protein electrophoresis showed a monoclonal spike in the gamma region. An IgG-kappa paraprotein was identified by immunofixation of the urine and serum. X-ray films of the bones revealed lytic areas in the skull, pelvis, and lumbar vertebrae. Bone marrow aspiration showed normal cellularity with 40% plasma cell infiltration. The patient was diagnosed with the IgG kappa type of multiple myeloma associated with acquired FVIII inhibitor. In patients presenting with severe bleeding, autoantibodies against FVIII should be considered for the differential diagnosis of bleeding. Clinicians should be alert to the presence of rare underlying neoplastic diseases such as multiple myeloma, in patients with acquired FVIII inhibitor.
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PMID:Multiple myeloma presenting with acquired factor VIII inhibitor. 1955 64

Although short activated partial thromboplastin times (APTTs) are generally considered to be laboratory artefacts of problematic blood collections, there is mounting evidence that in some cases a short APTT may reflect a hypercoagulable state, potentially associated with increased thrombotic risk and adverse cardiovascular events. We prospectively evaluated the phenomenon of short APTTs in 113 consecutive samples compared with an equal number of age and sex-matched normal APTT samples. We found a significant difference in various test parameters including prothrombin time (PT), Factor (F) V, FVIII, FXI, FXII, von Willebrand factor (VWF) antigen and collagen-binding activity, and in the level of procoagulant phospholipids, as assessed using a novel assay procedure (XACT). Interestingly, there was a significant negative association for fibrinogen, and although elevated, there was no significant association for FIX. On the basis of identified consecutive samples having multiple low APTTs on several sequential days, a proportion of laboratory-defined short APTTs appear to represent in-vivo hypercoagulability. In conclusion, plasma from patients presenting with short APTTs is reflective of a complex hypercoagulant milieu that could feasibly contribute to thrombotic risk, and 20% or more of laboratory definable short APTTs appear to reflect in-vivo phenomenon.
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PMID:A laboratory evaluation into the short activated partial thromboplastin time. 2005 42

HD1, a DNA aptamer, binds exosite 1 on thrombin and blocks its clotting activity. Because HD1 also binds prothrombin and inhibits its activation by prothrombinase, we hypothesised that HD1 would be a more potent inhibitor of coagulation than other exosite 1-directed ligands, such as Hir(54-65)(SO(3)(-)). Supporting this concept, the effect of HD1 on the prothrombin time and activated partial thromboplastin time was two-fold greater than that of Hir(54-65)(SO(3)(-)) even though both agents inhibited thrombin-mediated factor (F) V and FVIII activation to a similar extent. In thrombin generation assays, HD1 (a) delayed the lag time, (b) reduced peak thrombin concentration, and (c) decreased endogenous thrombin potential to a greater extent than Hir54-65(SO(3)(-)). To eliminate thrombin feedback, studies were repeated in FV- and/or FVIII-deficient plasma supplemented with FVa and/or FVIIIa. Only HD1 prolonged the lag time in FV- and FVIII-deficient plasma supplemented with FVa and FVIIIa. In contrast, HD1 and Hir54-65(SO(3)(-)) inhibited the lag time in FVIII-deficient plasma supplemented with FVIIIa and in normal plasma. The more potent anticoagulant properties of HD1, therefore, reflect its capacity to attenuate FV activation by thrombin and inhibit prothrombinase assembly. These findings identify prothrombin as a potential target for new anticoagulants.
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PMID:HD1, a thrombin- and prothrombin-binding DNA aptamer, inhibits thrombin generation by attenuating prothrombin activation and thrombin feedback reactions. 2006 17

Many reports have identified factor (F)VIII inhibitory antibodies with epitopes located in all subunits of the FVIII molecule. Antibodies that promote FVIII activity do not appear to have been reported. We characterised, for the first time, a unique anti-FVIII monoclonal antibody, mAb216, that enhanced FVIII coagulant activity. The mAb216 shortened the activated partial thromboplastin time and specifically increased FVIII activity by approximately 1.5-fold dose-dependently. FXa generation and thrombin generation were similarly increased by approximately 1.4- and approximately 2.5-fold, respectively. An A2 epitope, not overlapping the common A2 epitope, was identified and the antibody was shown to enhance thrombin (and FXa)-catalysed activation of FVIII by modestly accelerating cleavage at Arg(372). The presence of mAb216 mediated an approximately 1.5-fold decrease in K(m) for the FVIII-thrombin interaction. Enhanced FVIII activity was evident to an equal degree, even the presence of anti-FVIII neutralising antibodies with epitopes in each subunit. In addition, mAb216 depressed the rates of heat-denatured loss of FVIII activity and FVIIIa decay by 2 to approximately 2.5-fold. We have developed an anti-A2, FVIII mAb216 that augmented procoagulant activity. This enhancing effect could be attributed to an increase in thrombin-induced activation of FVIII, mediated by cleavage at Arg(372) and a tighter interaction of thrombin with the A2 domain. The findings may cast new light on new principles for improving the treatment of haemophilia A patients.
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PMID:Characterisation of an antibody specific for coagulation factor VIII that enhances factor VIII activity. 2006 22

Factor VIII, the plasma protein deficient or defective in individuals with hemophilia A, is a critical member of the blood coagulation cascade. Recent studies have identified the FVIII light chain region Glu1811-Lys1818 as being involved in FIXa binding and in the assembly of the FX-activating FIXaz-FVIIIa complex. Based on this, a series of 12 peptides, analogues of the 1811-1818 loop of the A3 subunit of the light chain A3-C1-C2 of FVIIIa, were synthesized and evaluated for their anticoagulant activity. Only peptide Ac-ETKTYFWK-NH(2) showed significant anticoagulant activity by inhibiting about 40% factor VIII at a concentration of 0.43 mM. It also showed a prolongation of activated partial thromboplastin time of 6.1 s, whereas its effect on prothrombin time measurements was meaningless. All the other peptides did not show any measurable effect at the concentration of 0.43 mM. These findings are encouraging though further investigation of the effect of this active peptide in different biological settings is needed in order to evaluate its possible clinical applications.
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PMID:Peptide analogues of 1811-1818 loop of the A3 subunit of the light chain A3-C1-C2 of FVIII of blood coagulation: biological evaluation. 2009 40


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