Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoantibodies towards coagulation factor VIII is a rare disease, incidence 1 pr. 2.5-5 million/year. The symptoms are most often subcutaneous or intramuscular haemorrhages or uncontrollable bleeding after minimal traumas. Screening tests show prolonged activated partial thromboplastin time, normal prothrombin time and thrombocyte count. Production of autoantibodies is controlled by prednisolone which may be supplemented with chemotherapy, i.e. azathioprine. Bleeding can be controlled by using coagulation factor concentrates that bypass factor VIII. If diagnosed early, there is a good chance of both stopping bleeding and suppressing autoantibody production. In order to be able to detect patients at risk of having factor VIII autoantibodies, it is recommended to screen all bleeding patients using activated partial thromboplastin time, prothrombin time and thrombocyte count. All patients showing isolated prolonged activated partial thrombin time should be referred to a laboratory specialized in coagulation problems for immediate evaluation.
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PMID:[Autoantibodies against coagulation factor VIII]. 980 May 8

Blood coagulation factor VIII (fVIII) in its nonactivated form circulates in plasma in a complex with von Willebrand factor (vWf). Upon activation by thrombin- or factor Xa-mediated site-specific proteolysis, activated fVIII (fVIIIa) serves as a cofactor for factor IXa. This protein complex assembled on a phospholipid surface (factor Xase) activates factor X. This complex plays the key role in the intrinsic pathway of blood coagulation. We reviewed the molecular events triggered by fVIII activation, which are required for the assembly and functioning of the Xase complex, including fVIIIa dissociation from vWf and a significant increase of fVIII affinity for binding to the phospholipid surface. Both events are mediated by activation-related cleavage within fVIII light chain (LCh), releasing the 40 amino-acid N-terminal LCh peptide, which is followed by a conformational change within the C2 domain. The conformational change within LCh is also required for the optimal fVIII cofactor functioning within the factor Xase complex, exerted via fVIIIa interactions with phospholipid, factor IXa, and factor X. Since factor IXa not only stabilizes but also proteolytically inactivates fVIIIa within the factor Xase complex, the stability of the membrane-bound fVIIIa in the presence and absence of factor IXa is discussed. In conclusion, we outline some new possible directions of the research. One of them arises from the recently demonstrated ability of plasma lipoproteins to provide a phospholipid surface for the assembly of the factor Xase complex in vitro. This finding raises a possibility that lipoproteins participate in factor Xase functioning in vivo and suggests a direct link between elevated levels of lipoproteins associated with atherosclerosis and increased thrombogenicity associated with this disease.
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PMID:Role of activation of the coagulation factor VIII in interaction with vWf, phospholipid, and functioning within the factor Xase complex. 1088 49

Blood coagulation factor VIII functions in the intrinsic pathway of blood coagulation as a cofactor by enhancing the assembly of its complex with factors IX and X on the surface of activated platelets. This requires factor VIII interaction with these two proteins, von Willebrand factor (vWF), and phospholipids on the platelet surface. Once factor VIII and factor IX are activated by proteolytic cleavage, the complex is able to activate factor X to factor Xa by proteolysis. In hemophilia A patients with severe factor VIII deficiency, about 30% respond to factor VIII infusion therapy immunologically to produce antibodies that inactivate the infused factor VIII and others that are noninhibitory. An assay that measures only the inhibitor antibodies demonstrated that the factor VIII A2, A3, and C2 domains are the most immunogenic, and domains A1 and B are poorly immunogenic or not immunogenic. The specific antibody responses to A2, A3, and C2 vary considerably among individuals, and epitopes for inhibitor antibodies have been determined for all three. The anti-C2 inhibitors prevent factor VIII binding to phospholipids and vWF, and anti-A3 inhibitors prevent binding to factor IX (IXa). An inhibitor binding site for factor X has been localized to the A1 domain acidic region, leading to inhibition of factor VIII/factor X binding by antibodies. This inhibitor mechanism is rare. Because a second binding site for factor IX was localized to the factor VIII A2 domain, it is likely but not proven that prevention of factor IX binding to factor VIII is the inhibitor mechanism for this epitope.
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PMID:Properties of anti-factor VIII inhibitor antibodies in hemophilia A patients. 1091 5

The interdomain acidic region a1 is a unique structural feature of coagulation factor VIII (FVIII) and may mediate the proteolytic activation of FVIII and the inactivation of FVIIIa. We report an individual with a Tyr346-->Cys substitution within region a1, who presented with a one-stage FVIII activity (FVIII:C) of 0.34 iu/ml (normal range 0.5-2.0) but normal two-stage FVIII:C and FVIII antigen values. In a factor Xa (FXa)-generation assay for FVIII in which the activation time with thrombin was varied, the variant plasma showed normal FVIII:C at both short and long activation times. However, at intermediate activation times the FXa generation of the variant plasma was less than that of normal pooled plasma. In a modified one-stage FVIII:C assay in which partially purified FVIII was activated with thrombin at low concentrations, the variant FVIII showed less activation than wild-type FVIII, although this defect corrected with increasing concentrations of thrombin. When partially purified variant FVIII was activated with a large molar excess of thrombin, the subsequent rate of decay of FVIII:C was greater for variant FVIII. The complex defects in activation and inactivation displayed by FVIII Tyr346-->Cys support the hypothesis that the a1 sequence is a key regulator of FVIII activity.
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PMID:A Tyr346-->Cys substitution in the interdomain acidic region a1 of factor VIII in an individual with factor VIII:C assay discrepancy. 1213 51

Large numbers of activated partial thromboplastin time (aPTT) reagents are sold in the market. The phospholipid content and its source, nature and the amount of activators are highly varied in different aPTT reagents. The present study was undertaken to evaluate which of the four aPTT reagents commonly used is suitable as an all-purpose reagent for a modest haemostasis laboratory. Four aPTT reagents (reagent A, Platelin LS; reagent B, Silimat; reagent C, Actin FSL; reagent D, CK Prest) were tested against 75 different plasmas obtained from normal patients as well as from patients with different haemostatic problems. All the tests were conducted by one of us (S.S.) in duplicates. Different aPTT reagents missed different proportions of mild factor VIII and factor IX deficiency (36.4, 18.2, 4.6 and 13.6% for reagents A, B, C and D, respectively) and showed abnormal results with normal plasmas (i.e. more than 5 s prolongation) (29.2, 25, 8.3 and 12.5% for reagents A, B, C and D, respectively). All the reagents faithfully picked up moderate and severe factor VIII and factor IX deficiency. There was no difference among the four aPTT reagents regarding their ability to prolong aPTT to therapeutic dosage of heparin or in their ability to give comparable factor VIII or factor IX levels in one-stage aPTT-based assays. There were differences in aPTT reagents in their ability to pick up mild deficiency of coagulation factor VIII and factor IX. Some reagents showed abnormal aPTT results in mild cases of factor VIII and factor IX deficiency without producing a large number of falsely prolonged aPTT with normal plasma.
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PMID:Comparison of four commercially available activated partial thromboplastin time reagents using a semi-automated coagulometer. 1285 37

Oxidatively modified low-density lipoprotein (OxLDL) is present in atherosclerotic lesions and has been proposed to play an important role in atherogenesis. Thrombosis is the major mechanism underlying acute complications of atherosclerosis. In the present study, we analyzed the interaction between OxLDL and blood coagulation factors, which are involved in the blood coagulation pathway. We investigated the effect of OxLDL on plasma coagulation by measuring prothrombin time (PT) as a parameter of the extrinsic pathway of blood coagulation and activated partial thromboplastin time (APTT) as a parameter of the intrinsic pathway of blood coagulation following the addition of OxLDL to plasma. OxLDL, but not native LDL, caused prolongation of APTT in a dose- and oxidation time-dependent manner. In addition, the oxidatively modified product of acetylated LDL (AcLDL), but not AcLDL, also caused prolongation of APTT. The inhibition of lysophosphatidylcholine production in OxLDL by phenylmethylsulfonyl fluoride or Pefabloc pretreatment of LDL resulted in a prolongation of APTT, which was equivalent to the effect of OxLDL. Moreover, OxLDL significantly inhibited blood coagulation factor VIII, IX, and XI activity. Furthermore, we demonstrated that recombinant factor VIII binds to OxLDL and that factor VIII associated with OxLDL is detected in the incubation mixture of OxLDL and plasma. These results indicate that the binding of factor VIII to OxLDL affects the intrinsic pathway of the blood coagulation cascade. The present study suggests that the interaction between OxLDL and factor VIII may provide important information on the initiation and progression of atherosclerosis.
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PMID:Inhibition of plasma coagulation through interaction between oxidized low-density lipoprotein and blood coagulation factor VIII. 1593 Jul 25

Hemophilia A is a congenital bleeding disorder characterized by a deficiency of coagulation factor VIII. Intramural hematoma of the colon is a very rare complication of this disease. We report a case of intramural hematoma of the cecum serving as the lead point of intussusception in a 65-year-old man with hemophilia A. The patient presented with right-sided abdominal pain and bloody stool. Palpation of his abdomen revealed a fist-sized mass. Abdominal computed tomography (CT) showed a circular mass with concentric rings, consistent with an intussuscepted intestine. Because his activated partial thromboplastin time (APTT) was prolonged, we gave him a continuous infusion of factor VIII during and after surgery. Laparotomy revealed an irreducible colo-colic intussusception and we identified a cecal hematoma as the lead point. After an unsuccessful attempt at Hutchinson's maneuver, we performed right colectomy. We report this case to illustrate the necessity of monitoring APTT in patients with hemophilia A who undergo surgery.
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PMID:Intramural hematoma of the cecum as the lead point of intussusception in an elderly patient with hemophilia A: report of a case. 1671 31

Hemophilia A affects male, whereas females are carriers and generally spared from this disease. However, we here reported a 65-year-old female with Hemophilia A while screening the gene mutation of coagulation factor VIII. The female went to hospital because of tripping to lead her right chest to be injured with subcutaneous hematoma. She had historically a hemorrhagic diathesis. The physical examination discovered her hip limited to bend and move, but no discrepancy length between her two legs. The initial laboratory tests showed that the activated partial thromboplastin time (APTT) was 61. 3 seconds (20-40 seconds), and the APTT corrected by mixing with normal plasma was 41.3 s, but the levels of PT, FIB and TT were normal. The plain radiographs revealed the hip joints to suffer from the acetabular dysplasia and osteoarthritis. The level of FVIII:C was 2%, F IX:C 200%, vWF:Ag 120%, vWF:Rcof 100%, vWF:CBA 128%, and the F VIII binding assay to vWF was normal. The primers for exon 14 of F VIII gene were designed according to the NM - 000132 gene sequence. DNA was abstracted from the patient blood. PCR were carried out and the DNA sequence was followed. A new mutation of 4111A-->C was discovered, which caused the amino acid sequence changed (T 1314 P). The mutation of T 1314 P may be the cause of this female patient to get the hemophilia A. This mutation was a novel one which has never been reported before.
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PMID:[Gene mutation analysis of coagulation factor VIII from a female patient with hemophilia A]. 1676 42

The chronic and immediate post-exercise responses in the hemostatic and fibrinolytic systems have been shown to be variable and reflect differing adaptations with ageing and responses to exercise protocols. This study investigated the effects of acute and exhaustive exercise on the amplitude and duration of hemostatic and fibrinolytic responses in young adolescent males. The sample comprised 10 sedentary boys (13.2+/-0.5 years, 55.8+/-11.3kg, 165.7+/-7.4cm), who had not exercised or received any medication for at least 2 weeks before the experiments. The subjects performed exhaustive stepping exercise, consisting of 1s up and down cycles to fatigue. When the subjects were unable to maintain the required stepping rhythm, they were given a 30s recovery period. Following each 30s recovery participants recommenced the stepping cadence until fatigue prevented them continuing. Venous blood samples were drawn before and immediately, 1 and 24h after exercise to assess the following coagulation and fibrinolytic parameters: Platelet counts, activated partial thromboplastin time (aPTT), prothrombin time (PT), coagulation factor VIII (FVIII:C), von Willebrand factor (vWF), fibrinogen concentration, thrombin-antithrombin complex (TAT), D-dimer, plasminogen activator inhibitor (PAI-1), and tissue-type plasminogen activator (t-PA). Immediately following exercise, platelet counts, aPTT, FVIII, vWF and t-PA were significantly elevated in contrast to PAI-1, which decreased significantly until 1h after exercise. FVIII and platelet counts were elevated at 1 and 24h after exercise, respectively. Only the parameters FVIII and PAI-1 did not return to baseline values during the first hour after physical exercise. When compared to adults the results revealed different rates and ranges of coagulation and fibrinolysis parameters being activated by exhaustive exercise in this group of adolescents.
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PMID:Hemostatic response to acute physical exercise in healthy adolescents. 1684 9

Oxidatively modified low-density lipoprotein (OxLDL) is present in atherosclerotic lesions and has been proposed to play an important role in atherogenesis. Asp-hemolysin, a hemolytic toxin from Aspergillus fumigatus, is a binding protein for OxLDL. This study was undertaken to clarify the biological activity of OxLDL and the potentially of Asp-hemolysin as a regulation factor to atherogenic effect by OxLDL. We first analyzed the interaction between OxLDL and blood coagulation factors, which are involved in the blood coagulation pathway. OxLDL caused prolongation of activated partial thromboplastin time (APTT) as a parameter of the intrinsic pathway of blood coagulation in a dose- and oxidation time-dependent manner. In addition, OxLDL significantly inhibited blood coagulation factor VIII, IX, and XI activity. Furthermore, we demonstrated that factor VIII binds to OxLDL. These results indicate that the binding of factor VIII to OxLDL affects the intrinsic pathway of the blood coagulation cascade. Next, to clarify the structure-function relationship of Asp-hemolysin, we expressed Asp-hemolysin in Escherichia coli as a fusion protein with a maltose-binding protein (MBP) and purified it by affinity chromatography. The purified recombinant Asp-hemolysin showed an immunoreactivity with the anti-Asp-hemolysin antibody. In addition, MBP-Asp-hemolysin fusion protein exhibited binding activity to Ox-LDL as did native Asp-hemolysin. Furthermore, to investigate the effect of the Asp-hemolysin-related peptide (P-21), a synthetic peptide derived from a region of Asp-hemolysin that is rich in positive charges, on macrophage proliferation induced by OxLDL. P-21 inhibited OxLDL-induced macrophage proliferation in a dose-dependent manner. In addition, the binding analysis of P-21 to OxLDL indicated that P-21 binds to OxLDL. These results indicate that P-21 inhibits the OxLDL-induced macrophage proliferation through binding of P-21 to OxLDL. In conclusion, we have shown that OxLDL affects the intrinsic pathway of blood coagulation, and its mechanism is dependent on the binding of factor VIII to OxLDL. Furthermore, we indicate the possibility that Asp-hemolysin is a useful tool to investigate the pathophysiological significance of OxLDL. In particular, since the P-21, an Asp-hemolysin-related peptide, inhibits the OxLDL-induced macrophage proliferation through binding of P-21 to OxLDL, further study on the binding mechanism between Asp-hemolysin-related peptide and OxLDL may provide important information on the prevention and treatment of atherosclerosis.
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PMID:[Biological activity of Asp-hemolysin as a regulation factor to atherogenic effect by oxidized low-density lipoprotein]. 1701 24


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