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At least 469 records · Page 26Linked to original sources
PubMed2006

Cryptic splice site usage in exon 7 of the human fibrinogen Bbeta-chain gene is regulated by a naturally silent SF2/ASF binding site within this exon.

In this work we report the identification of a strong SF2/ASF binding site within exon 7 of the human fibrinogen Bbeta-chain gene (FGB). Its disruption in the wild-type context has no effect on exon recognition. However, when the mutation IVS7 + 1G>T--initially described in a patient suffering from congenital afibrinogenemia--is present, this SF2/ASF binding site is critical for cryptic 5'ss (splice site) definition. These findings, besides confirming and extending previous results regarding the effect of SF2/ASF on cryptic splice site activation, identify for the first time an enhancer sequence in the FGB gene specific for cryptic splice site usage. Taken together, they suggest the existence of a splicing-regulatory network that is normally silent in the FGB natural splicing environment but which can nonetheless influence splicing decisions when local contexts allow. On a more general note, our conclusions have implications for the evolution of alternative splicing processes and for the development of methods to control aberrant splicing in the context of disease-causing mutations.

Base Sequence↗
PubMed1995

Techniques for evaluating the cause of bleeding in the ICU. Diagnostic clues and keys to interpreting hemostatic tests.

Begin by obtaining both a bleeding and a family history to help ascertain whether the disorder is acquired or inherited. On physical examination, look for multiple bleeding sites or profuse bleeding; these can indicate a systemic bleeding diathesis. Order hemostatic tests. Prolonged aPTT points to a defect in the intrinsic or common coagulation pathway; prolonged PT, to a defect in the extrinsic or common pathway. Thrombin time is abnormal when hypofibrinogenemia, afibrinogenemia, or thrombin inhibitors are present. Bleeding time is prolonged in thrombocytopenia, platelet dysfunction, severe hypofibrinogenemia, and von Willebrand's disease. Factor assays also may be needed to further define the defect.

Blood Coagulation Tests↗
PubMed1999

Real-time analysis of mural thrombus formation in various platelet aggregation disorders: distinct shear-dependent roles of platelet receptors and adhesive proteins under flow.

We evaluated real-time processes of platelet thrombus formation on a collagen surface in a flow chamber with whole blood from patients with various platelet aggregation disorders, such as Bernard-Soulier syndrome (BSS), Glanzmann's thrombasthenia (GTA), type 3 von Willebrand disease (vWD), and congenital afibrinogenemia (Af), who lack platelet glycoprotein (GP) Ib-IX complex, GP IIb-IIIa, von Willebrand factor (vWF), and fibrinogen, respectively. Blood from GTA patients showed impaired thrombus growth but significant initial platelet-surface interaction under all shear conditions tested (50 to 1,500 s(-1)). By contrast, blood from patients with BSS or type 3 vWD showed no platelet-surface interaction under high shear (>/=1, 210 s(-1)) but normal thrombus formation under low shear (</=340 s(-1)). When shear rate was increased stepwise to 1,500 s(-1) during perfusion, the thrombus growth observed in type 3 vWD or BSS under low shear was arrested, whereas that in control blood was sharply accelerated as a function of shear rate. Overall thrombus formation in Af appeared indistinguishable from that of a control under shear rates between 50 and 1,500 s(-1). However, Af thrombi formed under such conditions collapsed immediately when shear rate was further increased to 4,500 s(-1), whereas thrombi of type 3 vWD or BSS formed under low shear were stable even when shear rate was elevated to 9,000 s(-1) during perfusion. These findings suggest that distinct molecular mechanisms underlie the pathologic bleeding in these diseases and point to the distinct roles of two major adhesive proteins, vWF and fibrinogen. In mural thrombus formation under flow conditions, vWF, perhaps mainly through its interaction with GP Ib-IX, acts as an "initiator and promoter," whereas fibrinogen, via its binding to GP IIb-IIIa, acts as a "stabilizer" against heightened shear forces that could lead to peeling off of platelets from the surface.

Blood Coagulation Disorders↗
PubMed1999

Mechanisms underlying increased platelet reactivity in patients with peripheral arterial disease. Preliminary results.

BACKGROUND: In peripheral arterial disease (PAD) atherosclerosis is disseminated and thrombosis risk is high. We have not only shown the platelets of PAD patients to by hyperreactive and aspirin resistant, but have recently verified them to be hypersensitive to heparin as well. In the present study we have begun to clarify the mechanisms underlying these regularly observed clinical findings. METHODS: Platelet function was tested with conventional, ADP-primed aggregation and with stagnation point flow adhesio-aggregometry (SPAA). SPAA permits real time, quantitative assessment of platelet adhesion and aggregation under biologically relevant flow conditions. The platelets from a female patient with congenital afibrinogenemia, were analyzed before and after intravenous fibrinogen substitution. In 14 PAD patients and 14 controls, platelet reactivity was assessed before and after incubation with the two platelet membrane glycoprotein (GP)-IIb/IIIa inhibitors Ro 43-8857 and 7E3. Lastly, experiments were performed before and after addition of plasma aliquots stemming from 4 PAD patients to platelet rich plasma and to solutions of gel-filtered platelets (GFP) stemming from 4 healthy volunteers. Before fibrinogen substitution, the platelets of the afibrinogenemic patient were unable to adhere in the SPAA-system and maximal ADP-primed aggregability was below 10%. After substitution, normal platelet adhesion was measured and primed aggregation increased three-fold. Mean baseline adhesion in the patient collective was twice that compared to controls (p<0.001). SPAA-measured, spontaneous aggregation was observed in ten patients and in none of the controls (p<0.001). RESULTS: Both SPAA-measured and primed aggregation were abolished at the lowest substrate concentrations (0.1 microM Ro 43-8857, 1 microg/ml 7E3). At these concentrations adhesion was reduced by 65% and 40% (respectively) in patients, and by 55% and 25% in controls. Total abolition of adhesion in both groups was seen with 0.5 microM Ro 43-8857 and 10 microg/ml 7E3. Platelet response to inhibitory agent was similar in patients and controls, as were the differences in dose-response between aggregation and adhesion. Upon addition of patient plasma to volunteer PRP, the platelets of all 4 healthy individuals aggregated spontaneously and the mean adhesivity in the group rose three-fold. The overall ability of the GFP to adhere when re-added to their own plasma was decreased, whereas, in the presence of patient plasma, adhesion increased significantly. CONCLUSIONS: On the basis of these findings we conclude that: 1) SPAA measures and quantifies platelet interactions with both fluid-phase (aggregation) and immobilized (adhesion) fibrinogen, 2) these reactions are mediated by the GP, IIb/IIIa receptor complex 3) the binding affinity, metabolic pathways and signal transduction underlying platelet adhesion differ from those involved in aggregation (possibly reflecting their varying roles in hemostasis), 4) the functionally normal platelets of patients with PAD are primed in vivo by a circulating plasma constituent, which leads to enhanced recruitment of activated GP, IIb/IIIa onto the platelet surface and, thereby, to an overall increase in reactivity.

Acetates↗
PubMed2002

[Molecular variants of fibrinogen].

In the final step of blood coagulation, fibrin monomers polymerize spontaneously and are covalently linked by factor XIIIa. Mutations in one of the three genes coding for the fibrinogen peptides may disturb this process and lead to diseases such as afibrinogenemia or dysfibrinogenemia, or may even cause hereditary renal amyloidosis. In the brief overview presented here we summarize some of the molecular aspects of these diseases.

Amyloidosis↗
PubMed2002

The minimum concentration of fibrinogen needed for platelet aggregation using ADP.

OBJECTIVE: Determine the minimum concentration of plasma fibrinogen needed to stimulate the aggregation of platelets, collected from normal subjects, using ADP. DESIGN: Platelet rich plasmas (300 x 10(9) platelets/L) were made and adjusted to final fibrinogen concentrations of 75, 19, 5, and 0 mg/dL using fibrinogen free serum. Each fibrinogen concentration in all twelve subjects was aggregated with ADP SETTING: Research laboratory in the Department of Clinical Laboratory Science at Saint Louis University. PARTICIPANTS: Twelve healthy volunteers of both genders, between the ages of 18 and 60 years who were not pregnant and weighed at least 110 pounds were included in the study. Subjects were excluded from the study if they had ingested aspirin within one week prior to blood collection. In addition, subjects with a history of bleeding disorders such as afibrinogenemia, hypofibrinogenemia, von Willebrand disease, and Bernand-Soulier disease were rejected from the study. MAIN OUTCOME MEASURES: Platelet aggregation tracings were analyzed for amplitude and compared across plasma fibrinogen concentrations. In addition, the type of curve (monophasic vs. biphasic), smoothness and aggregation stability were also noted. RESULTS: The results show that aggregation occurred with every dilution of fibrinogen tested and that the amplitude of the aggregation curves appears not to be dependent on plasma fibrinogen. CONCLUSIONS: The results indicate that platelets from healthy individuals previously exposed to normal fibrinogen levels will aggregate equally well in decreasing plasma fibrinogen concentrations and even in the absence of plasma fibrinogen using ADP as the aggregator.

Adenosine Diphosphate↗
PubMed1992

[Platelet adhesion and adhesive proteins--how to measure the platelet adhesiveness].

We examined, platelet adhesive function in vivo by comparing the platelet retention rate (PRR) with other laboratory tests. In 71 patients, PRR did not correlate with bleeding time (BT), ristocetin-induced platelet agglutination (RIPA), vWF:AG, vWF:RCo, FVIII:C, fibrinogen, platelets counts or platelet aggregation tests. Among them, the coincidence rate of PRR with BT seems relatively better than that of other tests. In patients with Bernard-Soulier syndrome (BSS), PRR, RIPA and high shear-induced platelet aggregation (SIPA), measured using a cone-plate type instrument, were decreased, while platelet adhesion in a static system and SIPA at a low shear rate were normal. In patients with Glanzmann's thrombasthenia (TA), PRR and SIPA were decreased at both high and low shear rates, while RIPA and platelet adhesion were normal in a static system. In patients with deficient glycoprotein Ia/IIa complex which is one of the putative receptors for collagen, platelet adhesion in a static system is markedly decreased. In patients with von Willebrand disease, the pattern of platelet adhesion tests was similar to that of BSS patients, while in patients with afibrinogenemia, it was similar to that of TA patients except for SIPA at a high shear rate. The various experiments using monoclonal antibodies support these abnormalities. These findings, suggest that PRR is a suitable screening test, but further rapid and easy tests will be necessary to diagnose the defects of platelet adhesion at various shear rates.

Bleeding Time↗
PubMed2006

Solvent/detergent plasma for prevention of bleeding in recessively inherited coagulation disorders: dosing, pharmacokinetics and clinical efficacy.

BACKGROUND AND OBJECTIVES: This open-label multicenter trial of solvent/detergent (SD) plasma involving 17 patients with recessively inherited coagulation disorders (one afibrinogenemia, four FV, six combined FV and FVIII, one FX and five FXI deficiencies) evaluated the pharmacokinetics of the deficient factors and hemostatic efficacy. DESIGN AND METHODS: In vivo recovery (IVR) of the deficient coagulation factor was determined in a non-bleeding state in all patients and the mean values for FV, FVIII, FX, FXI and fibrinogen were 1.3, 1.2, 1.5, 1.3 and 1.5 dL/Kg, respectively. The mean plasma half-life of FV, FVIII and FX was 18, 43 and 33 hours, respectively. All patients underwent replacement therapy for elective procedures at risk of bleeding (surgery in 14 cases and vaginal delivery in two patients), except one treated for a central nervous system surgical emergency. RESULTS: Treatment courses with SD plasma were judged fully effective in 13/16 cases (81%). In the remaining three cases, mild bleeding occurred after major surgery in a FV deficient patient with a factor level of 43% and in a FXI deficient patient when factor levels were between 20% and 41%; and after minor surgery in a patient with FV and FVIII deficiency when factor levels were 41% and 18%, respectively. Bleeding was controlled by continuing or increasing treatment with SD plasma. INTERPRETATION AND CONCLUSIONS: These results suggest that, even though the current absolute risk of blood-borne infections associated with fresh-frozen plasma is relatively small, SD plasma should be preferred in patients with recessively inherited coagulation disorders who need replacement therapy when virus-inactivated single-factor concentrates are not available.

ABO Blood-Group System↗
PubMed1990

Congenital disorders of platelet function.

Platelets play a major role in normal hemostasis and congenital defects in platelet function are associated with bleeding manifestations that are largely mucocutaneous in origin and markedly variable in severity. They arise by different mechanisms and may be classified as disorders of: (1) platelet-agonist interaction, (2) platelet-vessel wall interaction (vWD and Bernard-Soulier syndrome), (3) platelet-platelet interaction (congenital afibrinogenemia and Glanzmann's thrombasthenia), (4) platelet secretion, and (5) platelet-coagulant protein interaction. Excluding vWD, most congenital platelet dysfunctions currently fall in the category of platelet secretion defects. Some of these patients have storage pool deficiency or defects in thromboxane synthesis, but the majority have normal granule stores. The underlying mechanisms in this large, heterogeneous group of dysfunctions remain to be elucidated. Bleeding episodes of vWD are managed by the administration of DDAVP or cryoprecipitate. The major treatment modality in the management of bleeding episodes and surgical procedures in patients with congenital platelet defects is platelet transfusions. Evidence is becoming available that many of these patients may respond to intravenous infusion of DDAVP with a shortening of the bleeding time. The specific groups of patients who will respond, and the efficacy of DDAVP in clinical situations remains to be established.

Arachidonic Acids↗
PubMed1978

Effect of shear rate on platelet interaction with subendothelium in citrated and native blood. I. Shear rate--dependent decrease of adhesion in von Willebrand's disease and the Bernard-Soulier syndrome.

Previous studies have demonstrated impaired adhesion of platelets to the subendothelium in von Willebrand's disease. These studies were performed by circulating (in a closed system) citrated whole blood through a chamber containing everted segments of rabbit aorta from which the endothelium had been removed by balloon catheter. The average wall shear rate was 800 sec-1, and the perfusion time was 10 min. In the present study we measured the interaction of platelets with subendothelium in native (nonanticoagulated) blood, using a recently described technique in which the vessel segments are perfused with directly sampled venous blood. The system was open; that is, the blood was not recirculated. We used blood flow rates of 20, 40, and 50 ml/min, which correspond to calculated shear rates of 1300, 2600, and 3300 sec-1 and perfusion times of 3, 2, and 2 min, respectively. For comparison, parallel studies at 1300 sec-1 were also obtained with citrated blood. In normal subjects, at a shear rate of 1300 sec-1, platelet adhesion was less in native blood than in citrated blood, but thrombus formation was greater. Platelet adhesion in five patients with von Willebrand's disease was decreased in both citrated and native blood. The magnitude of the adhesion defect was strongly dependent on the shear rate. Thus, in citrated blood studied at a shear rate of 1300 sec-1, adhesion was 75% less than in normal subjects, whereas in previous studies at 800 sec-1 the reduction in adhesion was 29%. In native blood, adhesion in von Willebrand's disease was normal at a shear rate of 1300 sec-1, whereas 53% and 77% reductions in adhesion were obtained at shear rates of 2600 and 3300 sec-1, respectively. The latter shear rates studied, adhesion of platelets in native blood was also decreased in the Bernard-Soulier syndrome but was normal in hemophilia and afibrinogenemia. Our findings with native blood provide further evidence that impaired adhesion of platelets to the vessel wall accounts for the hemostatic defect in von Willebrand's disease. In addition, this adhesion defect is shear rate-dependent.

Adolescent↗
PubMed1986

Alterations of the blood coagulation system after accidental human inoculation by Bothrops jararaca venom.

Blood coagulation studies carried out on 78 patients up to 30 h after they were bitten by Bothrops jararaca snakes demonstrated clotting defects in 37 patients which included afibrinogenemia, reduced levels of prothrombin, of factors V and VIII, thrombocytopenia and activation of the fibrinolytic system. Factor IX and X levels were within normal range for all patients. These in vitro data suggest that the disseminated intravascular clotting observed in vivo following envenomation may be triggered by the intravascular release of patient thrombin by snake venom enzymes.

Animals↗
PubMed1987

Effect of monoclonal antibodies against von Willebrand factor and platelet glycoproteins IIb/IIIa on the platelet retention test.

The platelet retention test provides a measure of the number of platelets retained in a column of glass beads and is one of the few in vitro platelet function tests that is abnormal in von Willebrand's disease (vWd). In a two-stage test, 1 mL of blood (designated A) was passed through the column, followed by 5 mL of isotonic saline and then 5 mL of blood (B) in which platelet retention was measured. With normal blood as A and B, retention is very high in all 5 mL of blood B. In the first stage, platelets adhere to the glass beads; this requires fibrinogen but not von Willebrand factor (vWf). The platelet-platelet adhesion in the second stage requires vWf, is dependent on release of ADP, and fails to occur if thrombasthenic platelets are tested. Retention was normal when blood from a patient with afibrinogenemia was used as blood B. We have now used monoclonal antibodies to elucidate further the mechanism of platelet retention. Five antibodies to different epitopes on vWf essentially abolished retention in the one-stage test and in the second stage of the two-stage test, but had no effect on the first stage. Thus, the entire vWf molecule must be free of antibody to function in the platelet-platelet adhesion of the second stage of this test. Binding of the antigen-antibody complex to the platelet Fc receptor was not responsible, as Fab and F(ab')2 fragments of one of the antibodies were as effective as intact antibody, and as neither heat-aggregated IgG nor a polyclonal antibody to plasma factor IX inhibited retention. F(ab')2 fragments of 6D1, an antibody to platelet GP Ib that prevents binding of vWf to platelets, also inhibited the second phase of retention. An antibody that inhibits binding of fibrinogen and vWf to GP IIb/IIIa (LJ-CP8) inhibited both the first and second stages of retention, whereas LJ-P5, an antibody that inhibits only the binding of vWf to GP IIb/IIIa, caused slight inhibition of retention when normal or afibrinogenemic blood was used as blood B and was reported to cause only partial inhibition of ADP-induced platelet aggregation in this afibrinogenemic patient. The results suggest that vWf is altered during rapid passage of blood through the glass-bead column so that it attaches to GP Ib, exposing GP IIb/IIIa, which then binds the altered vWf or fibrinogen, either of which can induce platelet aggregation (platelet-platelet adhesion) and thus retention in the column.

Antibodies, Monoclonal↗
PubMed1982

[Controlled substitution with blood products in hemostatic disorders].

It is essential for an efficient substitution to define the nature of the defect as good as possible. Simple screening tests allow a rapid classification. Prophylactic substitution is recommended in potentially reversible defects (bone marrow aplasia in connection with leukaemia treatment) and/or imminent bleeding (eventually complicated by additional risk factors). If bleeding cannot be stopped surgically therapeutic substitution is indicated. In case of bone marrow failure, a substitution may be particularly promising. In presence of an increased peripheral platelet destruction (disseminated intravascular coagulation, antithrombocytic antibodies) treatment of the basic disease is mandatory. Combined hemostatic defects can be influenced by fresh frozen plasma (FFP). Fresh whole blood (not older than 48 hours) may be considered in cases of thrombocytopenia and concomitant anemia. For isolated defects (e.g. hemophilias with or without antibodies, congenital afibrinogenemia, lack of factor XIII) special preparations are at hand. The clinical effect of substitution depends on the specific activity of the preparation, on the volume of expansion in the recipient and on other pharmacokinetic factors. Hepatitis and antibody-production may be considered as particularly grave side-effects.

Blood Coagulation Factors↗
PubMed1981

The endogenous lectin of human platelets is an alpha-granule component.

Platelets from patients with several bleeding disorders (congenital afibrinogenemia, Glanzmann's thrombasthenia, gray platelet syndrome, and Hermansky-Pudlak syndrome) were evaluated for both platelet-bound and platelet-free hemagglutination activities. Thrombin and A23187 activated afibrinogenemic, Hermansky-Pudlak, and thrombasthenic platelets had normal platelet-bound hemagglutination activity. Gray platelets activated by the same agents had deficient platelet-bound hemagglutination activity. In contrast, thrombin-activated afibrinogenemic, gray, and thrombasthenic platelets lacked platelet-free hemagglutination activity. Only thrombin-activated Hermansky-Pudlak platelets had a normal level of platelet-free hemagglutination activity. On the basis of these results and the distinguishing characteristics of the defective platelets, it is concluded that the alpha-granules are the origin of the enhanced hemagglutination activity. Furthermore, it is suggested that the insufficiency of the platelet-bound agglutinin may be the cause of the inability of gray platelets to aggregate normally in response to thrombin.

Blood Coagulation Disorders↗
PubMed1995

Desmin 370, a low molecular weight dermatan sulfate, reduces the weight of preformed thrombi in rats made afibrinogenemic by ancrod.

Desmin 370 (D370), a low molecular weight dermatan sulfate, has been shown to induce a marked reduction of the weight of preformed venous thrombi in rats and rabbits by mechanisms that appeared largely independent of inhibition of thrombus accretion. In order to provide further support for such a mechanism, we exploited the defibrinating capacity of ancrod to obtain a thrombosis model characterized by the lack of thrombus growth and thus sensitive only to agents promoting thrombus lysis. Thrombus formation in anesthetized rats was induced by vena cava ligature. Injection of ancrod (5 U/kg) 5 h after induction of venous stasis caused a more than 95% reduction in plasma fibrinogen and prevented thrombus accretion as indicated by the lack of thrombus weight increase during the 3 h experimental period (12.2 +/- 0.6 vs 14.5 +/- 1 as compared to 12.6 +/- 0.6 vs 19.6 +/- 0.8, p < 0.01, in control rats) and by the almost complete (> 90%) inhibition of 125I-fibrin(ogen) binding to thrombi. Moreover, when ancrod was given 1 h before vena cava ligature, no thrombi were formed within 2 h whereas at the same time interval visible thrombi were present in all control rats. Administration of D370 (10 mg/kg) to thrombus bearing rats, 1 h after induction of afibrinogenemia, resulted in a significant reduction in thrombus weight (43% after 2 h, p < 0.01) which was only slightly lower than that recorded in normofibrinogenemic rats (54%). Enhancement of plasma fibrinolytic activity by ancrod had no influence on thrombus lysis and was not all affected by administration of D370.(ABSTRACT TRUNCATED AT 250 WORDS)

Ancrod↗
PubMed1993

Hemophiliacs--a picture from a developing country: Karnataka, a south Indian state.

Forty cases of hereditary bleeding disorders, who are the members of Karnataka Hemophilia Society (a State Chapter of the Hemophilia Federation of India) were studied to learn their problems. Twenty-four cases were thoroughly investigated including factor assay and in 16 cases the diagnosis was based on classical clinical presentation and pattern of inheritance. There were 16 cases of hemophilia A, 3 cases of hemophilia B, 2 cases of von Willebrand's disease, 1 case of factor XIII deficiency and 2 cases of hereditary afibrinogenemia. The age group varied from 3 months to 36 years; 39 were male. The age of onset of symptoms, type of bleeding, type of joints involved, disabilities experienced by these patients, severity of the disorder, presence of antibodies to factor, presence of HBsAg and HIV, the availability of treatment for these patients, treatment received and the financial burden faced by these patients were studied. Thirty-three cases (82.5%) had joint bleeds, 60% of the patients experienced various type of disabilities, 11 (27.5%) had epistaxis, 10 (25%) had GI bleeds, 5 (12.5%) had dental bleeding, 8 (20%) had haematomas, 3 (7.5%) had umbilical stump bleeds and 19 cases (47.5%) had previous blood transfusions.

Adolescent↗