Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684275 (haemophilia)
 10,958 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two fibronectin (FN)-containing blood products, human peripheral blood plasma and cryoprecipitate, were examined for their effect on mitogen-induced lymphocyte transformation in vitro. Responses of human peripheral blood lymphocytes to phytohemagglutinin (PHA) were depressed in the presence of a plasma concentration above that required for maximum DNA synthesis, and this concentration must be present in cultures prior to lymphocyte activation. The removal from the plasma of heparin-induced cryoprecipitate, a complex consisting of FN, heparin, and fibrinogen, resulted in a significant reduction in the inhibitory effect of the plasma on the PHA response. Plasma specifically depleted of FN by affinity chromatography on gelatin-agarose beads was 32 percent less inhibitory to the PHA-induced stimulation of cells than untreated plasma; the remaining inhibitory activity in the FN-depleted plasma samples was attributed to the presence of other normal immunosuppressive factors. The inhibitory capacity of FN in plasma was similar to that obtained with purified FN alone, which indicates that, unlike that of other known plasma inhibitors, the immunosuppressive activity of FN was not altered by the presence of other components of plasma. Cryoprecipitate used in the treatment of hemophilia contains high levels of FN, and, as anticipated, PHA-induced lymphocyte transformation was markedly depressed in the presence of solubilized cryoprecipitate. The contribution of FN to the T-cell abnormalities in patients chronically receiving cryoprecipitate and/or factor VIII concentrates derived from cryoprecipitate warrants further investigation.
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PMID:Influence of fibronectin-containing blood products on lymphocyte reactivity. 217 78

A fast migrating protein (FMP) was detected by agarose radio-crossed immunoelectrophoresis, in addition to factor VIII antigen (VIII:RAg), using antiserum to human factor VIII (FVIII). FMP had partial immunochemical identity with FVIII, migrated as an alpha-protein, and was distinct from alpha-2 macroglobulin, fibronectin or IgM. FMP was precipitated by concanavalin A and was separable from the bulk of VIII:RAg by ammonium sulphate fractionation. A significant amount of FMP was seen in normal serum (n = 12), plasma from patients with: (a) disseminated intravascular coagulation (n = 12) and (b) severe haemophilia A (n = 6). Trace amounts of FMP were observed in plasma from normal donors (n = 12), but neither VIII:ARg nor FMP was detectable in the plasma or serum from patients with severe von Willebrand's disease (n = 3). Freshly prepared cryoprecipitate contained trace amounts of FMP, similar to normal plasma, but increased levels were observed in antihaemophilic factor concentrates prepared for patient use. Significant levels of FMP were also seen in cryoprecipitate after storage at 4 degrees C for 7 d and this generation of FMP was diminished by the addition of protease inhibitors. The presence of significant levels of FMP in situations where proteolytic enzymes may be activated and inhibition of its generation by protease inhibitors, suggest that this protein is produced by proteolytic action of enzyme(s) on the FVIII molecule.
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PMID:Fast migrating protein, immunochemically related to human factor VIII, studied by crossed immunoelectrophoresis in agarose. 640 77

Studies on the effect of DDAVP both in vitro and in vivo are reported. In order to define the extent of the DDAVP induced rise of circulating endothelial cell proteins in normal individuals and the endothelial cell defect in von Willebrand's disease (vWd) we have measured the effect of intravenous DDAVP on a range of possible endothelial cell markers in normal subjects and in patients with mild haemophilia and vWd. In a series of double blind cross over studies on normal volunteers we have tested the effect of naloxone, DDAVP or saline on circulating levels of factor VIII related activities (VIIIR) and plasminogen activator (PA). The results confirmed the effect of DDAVP on circulating levels of VIIIR and PA but showed that it did not induce release of these activities from cultured endothelial cells in vitro nor did it influence circulating levels of other endothelial cell markers including fibronectin, antithrombin III and platelet factor 4. Infusion of nalaxone did not significantly alter circulating levels of VIIIR or PA nor the response of these to DDAVP suggesting that normally these activities are not subjected to a vasopressin drive.
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PMID:The effect of desamino-D-arginine vasopressin (DDAVP) and naloxone infusions on factor VIII and possible endothelial cell (EC) related activities. 643 Mar 37

Monoclonally purified factor concentrates have been available for hemophilia treatment since the late 1980's. They are biochemically characterized by a high-degree of clotting factor (FVIII or FIX) purification and by the virtual lack of contaminants (immunoglobulins, fibrinogen and fibronectin). The purification procedure sharply reduces the viral load and increases the safety of the concentrate because of the viral inactivation procedures. Viral safety is demonstrated by prospective studies in previously untreated patients as well as by the huge amount of concentrates produced and used so far without reports of untoward side effects. Monoclonal concentrates are also safe in terms of inhibitor production: they do not elicit the appearance of inhibitors to either FVIII or FIX with increased frequency, as shown by data in published prospective studies. Prospective studies have recently demonstrated that the long-term administration of these high purity concentrates does not exert any side effects on the immune system in HIV-positive hemophiliacs. The FIX concentrate is also extremely safe in terms of thrombotic complications: the highly pure FIX does not activate blood coagulation. It has been shown that the monoclonally purified FIX concentrate caused no thrombotic events in high-risk surgical patients who had previously experienced such complications while on Prothrombin Complex Concentrates.
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PMID:Immunopurified clotting factor concentrates. 817 18

Protein A is extracted from a strain of Staphylococcus aureus and binds specifically to the constant domains of immunoglobulins and possibly to fibronectin. It has already been shown that concentrations of all IgG isotypes (except IgG3) are efficiently decreased by immunoadsorption (IA) on protein A linked to sepharose beads. This system has been developed by Cobe-Excorim Co. to either remove IgG in some instances where they wil be harmful, i.e. allo- and autoantibodies inducing pathological conditions (autoimmune diseases, haematological disorders with allo/autoantibodies, anti-HLA antibodies in sensitized patients awaiting organ transplantation) or treat several immunological diseases with unknown pathogenesis. In our unit, 20 patients with high titres of anti-HLA panel-reactive antibodies, four patients with haematological disorders (haemophilia with anti-VIII antibodies and Glanzmann diseases) and three patients with post-transplant focal glomerular sclerosis (FGS) underwent IA over the past 5 years. Infectious complications were not observed after IA and the procedure was always well tolerated. In spite of the use of adjunctive immunosuppressive therapy with prednisone and cyclophosphamide, and although the reduction in serum IgG was close to 90%, the de novo synthesis of allo- and autoantibodies was important after IA procedures. In the cases of removal of anti-HLA antibodies, patients with a pre-IA antibody titre which was > 1:128 clearly did not benefit from the technique and other immunological criteria were not predictive of efficacy. Fourteen patients were transplanted, four with a well-matched kidney with both pre- and post-IA negative cross-matching, and 10 with a positive historical cross-match with the donor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Five years' experience at one centre with protein A immunoadsorption in patients with deleterious allo/autoantibodies (anti-HLA antibodies, autoimmune bleeding disorders) and post-transplant patients relapsing with focal glomerular sclerosis. 852 77

Patients with haemophilia often exhibit a variety of disturbances in immune function. Although infections with HIV, hepatitis and other viruses no doubt contribute to these abnormalities, chronic exposure to extraneous proteins in clotting factor concentrates (CFCs) may also play a role. Numerous in vitro and ex vivo studies show that protein contaminants--such as immunoglobulins, fibrinogen and fibronectin--can depress various immune function indicators. Generally, such studies show that intermediate-purity CFCs are more inhibitory than very high-purity (e.g. monoclonal-purified) CFCs. In many, but not all, studies, the degree of immunosuppression correlates with the amount of intermediate-purity CFC administered over time. Among various indicators of immune function, CD4+ lymphocyte number is a marker for the progression of HIV infection, and maintenance of CD4+ number is associated with delayed progression. A number of studies suggest that, compared with intermediate-purity CFCs, use of very high-purity CFCs is associated with longer preservation of this class of lymphocytes. However, it remains to be seen whether this translates to improved long-term clinical outcomes. Further research is needed on the impact of CFCs on the immune system. For the time being, however, evidence to date favours the use of very high-purity products because they appear to preserve immune function and reduce the risk of infection with hepatitis and other viruses.
Haemophilia 1998 Sep
PMID:Clotting factor concentrates and immune function in haemophilic patients. 987 75

The PFA-100 is a new platelet function analyzer which uses whole blood and high shear stress blood flow to simulate primary hemostasis and assess platelet function. A small volume of blood is introduced into a disposable cartridge, and forced through a capillary tube. Platelet adhesion and aggregation is then initiated following exposure to either collagen/ADP [C/ADP] or collagen/epinephrine [C/Epi] coated membranes. Movement of blood through the capillary, and its subsequent occlusion is monitored and yields the measured endpoint (closure time [CT] in seconds). Using two approaches, we assessed the sensitivity of this system to disturbances in the function of von Willebrand Factor (VWF). Firstly, we assessed the ability of the PFA-100 to detect the presence of von Willebrands Disease (VWD). Using normal individuals (N = 18), CTs (in seconds; mean [range = mean +/- 2SD]) were (i) C/ADP, 95 [66-124], (ii) C/Epi, 128 [98-158]. A panel of 47 patients undergoing evaluation for clinical hemostatic defects inclusive of VWD were also evaluated. All samples from patients confirmed to have VWD following specific VWF studies [N = 9; 3 x Type 1, 1 x Type 3, 1 x Type 2A, 4 x Type 2B] gave prolonged CTs (>/= 200 s) for both C/ADP and C/Epi membranes; in contrast, all patients yielding normal CT values were found to yield normal VWF results (i.e., were found not to suffer from VWD). Patients with hemophilia (1 x hemophilia A, 1 x hemophilia C) gave normal PFA-100 CT, while those with clinical thrombocytopaenia (N = 3) gave prolonged PFA-100 CT. A number of other patient samples also gave abnormal CT values which in some cases could be linked to recent aspirin consumption. In the second evaluation process, and using normal blood, we have assessed the ability of various antibodies to influence the CT. Of the monoclonal antibody panel tested [N = 20], only a proportion of those against VWF [6/10] or gp1b/IX [CD42; 2/5] were found to be inhibitory (i.e., prolonged the CT). Data using polyclonal antibodies (against platelets, VWF, fibrinogen and fibronectin) is more complex but largely confirms the sensitivity of the system to VWF. On the basis of these results, we conclude that the PFA-100 is highly sensitive to disturbances in VWF and to the presence of VWD and may thus provide a valuable screening test for VWD in certain specific circumstances (i.e., acute need conditions or remote testing sites; normal CT result generally effective as negative predictor, i.e. not severe VWD). However, since abnormal CT values were obtained in clinical situations other than evident VWD, the PFA-100 cannot be used as a specific diagnostic tool to establish the presence of VWD. Thus, any abnormal PFA-100 CT result should be thoroughly evaluated by follow-up specific testing to establish the true clinical disorder affecting the individual under investigation, inclusive of appropriate VWF assays if VWD is clinically suspected.
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PMID:Use of a novel platelet function analyzer (PFA-100) with high sensitivity to disturbances in von Willebrand factor to screen for von Willebrand's disease and other disorders. 1053 83