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Biomedical subjects

J Chediak

Publications and source records attributed to J Chediak.

At least 19 recordsLinked to original sources
PubMed2000

Activated recombinant human coagulation factor VII (rFVIIa) therapy for abdominal bleeding in patients with inhibitory antibodies to factor VIII.

Eight patients with inhibitors to factor VIII (4 hemophilia A and 4 nonhemophilic) were treated with recombinant activated factor VII (rFVIIa) to control severe abdominal bleeding. The recombinant factor was supplied under an open-label, emergency-use program to patients previously unresponsive to one or more alternative therapies. Therapy with rFVIIa was administered for nine separate bleeding events; one patient was treated for two separate bleeding episodes. Patients were treated for an average of 9 days and received a mean total dose of 5.2 mg of rFVIIa for control of bleeding. Treatment was considered successful and hemostasis adequate in 7 of the 9 episodes (78%). Treatment with rFVIIa was partially successful in one other episode. Four patients in this series experienced serious adverse events; all the adverse events were considered unrelated to rFVIIa therapy. The results of this limited series indicate that rFVIIa is an effective means of managing life-threatening abdominal bleeding in individuals with hemophilia or acquired antibodies to factor VIII.

Abdomen↗
PubMed1992

Diffuse alveolar hemorrhage secondary to superwarfarin ingestion.

A 27-year-old woman with severe vitamin K deficiency presented with hemoptysis and diffuse pulmonary infiltrates. She rapidly developed respiratory failure requiring ventilatory support. Surreptitious ingestion of brodifacoum, a long-acting warfarin derivative, was ultimately found to be the cause of her coagulopathy and DAH.

4-Hydroxycoumarins↗
PubMed1991

The role of von Willebrand factor in pre-eclampsia.

The von Willebrand factor (vWF) has gained considerable interest in recent years as a marker of endothelial cell activation or insult and by virtue of its interactions with platelets and vessel walls. Altered patterns of vWF multimers were found to occur frequently in patients with thrombotic thrombocytopenic purpura in the acute and chronic stages. This disorder shares some clinical and laboratory findings with pre-eclampsia, including thrombocytopenia. Recent studies have also suggested that abnormalities of endothelial cell metabolism play a central role in the pathophysiology of pre-eclampsia. In order to determine if vWF could be instrumental in the disease process and the thrombocytopenia of pre-eclampsia we analyzed the ante- and postpartum structural and functional distribution of vWF. This data was correlated with hematological parameters such as platelet counts and the clinical severity of the disease. We found no consistent changes of vWF in association with thrombocytopenia or clinical severity. However, functional vWF was lower in postpartum samples of severely affected pre-eclamptics as compared to normal controls. This finding may reflect endothelial cell exhaustion after stimulation or cellular injury. Elevated titers of fibrin split products and thrombocytopenia were evident in severe pre-eclampsia, as seen in DIC, despite factor VIII coagulant levels within the normal range. Our data is consistent with the hypothesis of endothelial cell dysfunction in pre-eclampsia. However, the mechanism of thrombocytopenia in this disorder does not appear to be related to alterations in the structure or biological function of vWF.

Adult↗
PubMed1991

Quantitative and qualitative platelet abnormalities during pregnancy.

In a 1-year period, 15 of 4048 pregnant women were found to have thrombocytopenia during their first prenatal visit. Their qualitative and quantitative platelet abnormalities were followed up prospectively for 1 to 6 months post partum. Platelet counts returned to normal in 14 of 15 patients 4 to 6 weeks post partum. von Willebrand factor antigen and ristocetin cofactor activity were low in three of 15 patients 4 to 6 weeks post partum, but had been normal during the antepartum period. Two of these three patients had prolonged bleeding times ante partum and post partum. All three patients subsequently were found to have mild type I von Willebrand disease. Six patients had detectable platelet antibodies. Neonatal thrombocytopenia was found in one term infant of a patient with mild thrombocytopenia and negative platelet antibodies. This study suggests that mild, transient, isolated thrombocytopenia can occur in an otherwise normal pregnancy and its incidence may be lower than previously reported. Extensive testing is not indicated unless there is an associated prolonged bleeding time. The possibility of von Willebrand disease or a qualitative platelet disorder should be considered.

Adolescent↗
PubMed1988

Further evidence of von Willebrand factor involvement in thrombotic thrombocytopenia purpura.

Fourteen patients diagnosed as having thrombotic thrombocytopenia purpura (TTP) were studied. Those who survived have been followed during a 1 to 7 year period. The clinical diagnosis was based on changing neurological findings, thrombocytopenia and evidence of microangiopathic hemolytic anemia. Laboratory tests included the determination of von Willebrand factor antigen (VWF:Ag), ristocetin cofactor (RiCof) and the electrophoretic mobility of von Willebrand factor (CIE VWF:Ag). The ratio of RiCof to VWF:Ag was then calculated. Control individuals included healthy subjects and patients with thrombocytopenia of several etiologies. Statistical differences between the values of RiCof, the ratio of RiCof:VWF:Ag and the CIE of VWF:Ag were found for samples comparing active disease and remission phase. The recovery from thrombocytopenia paralleled the correction of abnormal parameters. Similarly, significant differences were found when above parameters were compared between thrombocytopenia of TTP with other thrombocytopenic states. We suggest that these abnormal tests could be useful in distinguishing TTP from other disorders, and may have prognostic significance in patients already diagnosed as having TTP.

Adolescent↗
PubMed1987

Expression of abnormal von Willebrand factor by endothelial cells from a patient with type IIA von Willebrand disease.

Studies were conducted to characterize the biosynthesis of von Willebrand factor (vWf) by cultured endothelial cells (EC) derived from the umbilical vein of a patient with type IIA von Willebrand disease. The patient's EC, compared with those from normal individuals, produced vWf that had decreased amounts of large multimers and an increase in rapidly migrating satellite species, features characteristic of plasma vWf from patients with type IIA von Willebrand disease. The type IIA EC did produce a full spectrum of vWf multimers in both cell lysates and postculture medium, although the relative amounts of the largest species were decreased. The large multimers were degraded in conjunction with the appearance of rapidly migrating satellites that contained approximately equal to 170-kDa proteolytic fragments, suggesting that this patient's functional defect is due to abnormal proteolysis and not to a primary failure of vWf subunit oligomerization. Moreover, the observed degradation appears to result from an abnormal vWf molecule and not elevated protease levels. These results suggest that this patient's von Willebrand disease phenotype is caused by increased proteolytic sensitivity of his vWf protein.

Cell Division↗
PubMed1986

Studies on a circulating anticoagulant inhibiting factor XI in a patient with congenital deficiency and carcinoma of the prostate.

An inhibitor of plasma thromboplastin antecedent (PTA, factor XI), measured in coagulant and radioimmunoassays, was detected in a 60-year-old man with carcinoma of the prostate who had no evidence of a bleeding tendency. Family studies indicated that the patient was either a homozygote or a heterozygote for hereditary factor XI deficiency. In contrast to earlier described patients with factor XI deficiency in whom inhibitors were detected, the patient was unaware of having been transfused with blood or blood products at any time before the discovery of the inhibitor. The inhibitor of factor XI in the patient's plasma appeared to be predominantly in the IgG4 fraction and to be directed at a locus on the factor XI molecule other than the active site; it did not block the amidolytic properties of activated factor XI (XIa). Rather, it appeared to block adsorption of factor XI to negatively charged surfaces. The inhibitor interfered with measurement of other components of the intrinsic pathway of thrombin formation, perhaps explaining the low titres of other coagulation factors of the intrinsic system reported in patients with strong inhibitors directed against factor XI.

Factor XI↗
PubMed1986

Carrier detection in hemophilia A: a cooperative international study. I. The carrier phenotype.

Eight laboratories in six countries cooperated to clarify several issues concerning the phenotypes of heterozygous carriers of hemophilia "A." Plasma levels of factor VIII (F.VIII:C, formerly VIII:C) and von Willebrand factor (VWF:Ag, formerly VIIIR:Ag) of carriers and normal women were determined by various "in-house" methods; a single lyophilized plasma standard was used for all assays. Analysis of the collated data from 336 carriers (296 obligatory carriers and 40 sporadic carriers) and 137 normal women showed that there was no difference in the F.VIII:C levels of "paternal" carriers (women who had obtained the abnormal gene from their fathers) and "maternal" carriers. Neither was there a difference in the VWF:Ag levels of normal women and either type of carrier. Age was found to have a significant effect on both F.VIII:C and VWF:Ag, values being higher at very young and very old ages, the minima occurring in the 25- to 30-year range. ABO blood type had a striking effect. Women of types A, B, and AB (designated non-O in the study), both normals and carriers, had significantly higher levels of both factors than did women of type O. Analysis by laboratories showed that differences in mean levels of both factors between laboratories were highly significant. It was concluded that age, ABO blood type, and laboratory variation should be taken into account in carrier detection.

ABO Blood-Group System↗
PubMed1986

Carrier detection in hemophilia A: a cooperative international study. II. The efficacy of a universal discriminant.

Factor VIII (F.VIII) and von Willebrand factor (VWF):Ag data collected by eight laboratories on a total of 336 obligatory carriers of hemophilia A and 137 normal women were used to answer several questions concerning the construction of linear discriminants for carrier detection. It was found: that a "universal" linear discriminant can be constructed which is suitable for use in all laboratories and is nearly as effective as laboratory-specific discriminants; that inclusion of age and ABO blood type data improved the efficacy of these discriminants; that substitution of alternative assays for F.VIII and VWF:Ag did not generally improve the efficacy of the discriminants over that obtained using the bioassay for F.VIII:C and Laurell's immunoassay for VWF:Ag; that linear discriminants were far more effective than discriminants based on the F.VIII:C/VWF:Ag ratio. A step-wise procedure is given which any laboratory may follow in using the universal discriminant for carrier detection.

ABO Blood-Group System↗
PubMed1984

Pulmonary function in hemophiliac patients treated with commercial factor VIII concentrates.

Pulmonary function was tested before and after the administration of a commercial preparation of factor VIII concentrate in 20 patients with hemophilia A. The material was infused through the filter provided by the manufacturer, which is supposed to remove particles larger than 170 mu. Baseline information showed that patients who smoke had a lower pulmonary diffusing capacity for carbon monoxide than nonsmokers (22.9 +/- 4.2 ml/minute/mm Hg, p less than 0.01). The administration of factor VIII was not associated with clinical abnormalities. There was a small reduction in carbon monoxide diffusing capacity (27 +/- 5.8 to 26.2 +/- 5.9 ml/minute/mm Hg, p = 0.03), which was no longer significant after carbon monoxide diffusing capacity was corrected for lung volume (5.66 +/- 1.32 to 5.54 +/- 1.34, p greater than 0.06). This study does not support the need for 40 mu filtration of factor VIII concentrate.

Adolescent↗
PubMed1983

Gel filtration patterns of factor VIII coagulant antigen and factor VIII related antigen in normal and von Willebrand's disease.

Gel filtration (sepharose 2B CL) patterns of factor VIII coagulant antigen (VIIIC:Ag) and factor VIII related antigen (VIIIR:Ag) were obtained using normal plasma and plasma from patients with von Willebrand's disease. The latter group consisted of five individuals with normal mobility of factor VIIIR:Ag on cross-immunoelectrophoresis (Type I) and five others with abnormal (increased) mobility (Type II). Results showed that the elution of VIIIC:Ag was delayed in those subjects whose ratio of VIIIR:Ag to VIIIC:Ag was reduced. It has previously been reported that VIIIR:Ag exerts a stabilizing influence on the coagulant activity of factor VIII (VIII:C); our data suggests that when VIIIR:Ag is deficient, abnormal (low molecular weight) forms of VIIIC:Ag circulate.

Antigens↗
PubMed1983

Reduced surface expression and binding of fibronectin by thrombin-stimulated thrombasthenic platelets.

Thrombin stimulation results in increased surface expression of endogeneous fibronectin and binding of plasma fibronectin to human platelets. Platelets of patients with Glanzmann's thrombasthenia, a bleeding disorder, exhibit reduced thrombin-induced platelet aggregation, little or no clot retraction, and abnormal platelet spreading on glass surfaces. Thrombin stimulation of patient platelets from four thrombasthenic kindreds resulted in little fibronectin binding. Nevertheless, thrombin did induce serotonin secretion from these cells, indicating that stimulation was occurring. Thrombasthenic platelets did not inhibit thrombin-stimulated fibronectin binding to coincubated normal cells, suggesting that their defect was not due to the presence of a soluble inhibitor of fibronectin binding. Thrombin-stimulated afibrinogenemic platelets bound similar quantities of fibronectin to normal cells, indicating that the thrombasthenic deficit is not secondary to reduced fibrinogen content or binding. The thrombasthenic cells had an endogenous fibronectin content of 2.9 +/- 0.7 micrograms/10(9) platelets, whereas cells simultaneously prepared from five normal individuals contained 1.8 +/- 0.7 micrograms/10(9) platelets, a statistically insignificant difference. Nevertheless, thrombin stimulation did not increase expression of endogeneous fibronectin antigen on the surface of the thrombasthenic platelets as judged by immunofluorescence. These defects in platelet fibronectin binding and surface expression may account for some of the manifestations of Glanzmann's thrombasthenia.

Binding Sites↗
PubMed1983

Antithrombin "Chicago": a functionally abnormal molecule with increased heparin affinity causing familial thrombophilia.

A family with a high incidence of spontaneous thromboembolism over four generations has been investigated. The propositus is a 21-yr-old male with a history of thrombophlebitis. Medical histories of 46 family members were obtained. Twelve of these individuals have experienced deep venous thromboses and/or pulmonary emboli. Seven members of the kindred, with a prior history of thrombotic phenomena, were investigated in detail. These subjects were found to have normal plasma concentrations of immunoreactive antithrombin (mean 96%), decreased plasma levels of progressive antithrombin activity (mean 50%), and greatly reduced amounts of plasma heparin cofactor activity (mean 42%). The abnormal antithrombin ("Chicago") was found to elute from heparin-Sepharose at a higher ionic strength than normal inhibitor. The functionally defective antithrombin molecules exhibit a reduced ability to neutralize thrombin in the presence or absence of heparin (approximately 10%-20% of normal). The molecular defect of this protease inhibitor thus appears to be distinct from those of previously described abnormal antithrombins.

Adult↗
PubMed1981

Fibronectin in von Willebrand's disease and thrombasthenia: role in platelet aggregation.

Fibronectin is involved in cell-cell and cell-substratum adhesion processes. Since von Willebrand's disease and thrombasthenia are characterized, respectively, by platelet-substratum and platelet-platelet adhesion anomalies, we investigated the state of fibronectin in platelets and plasma of these two disorders as well as the role of plasma fibronectin in platelet aggregation. The levels of platelet and plasma fibronectin in three cases of von Willebrand's disease and in three cases of thrombasthenia did not show statistically significant differences as compared with the normal controls. Immunofluorescent staining intensity and patterns of disease-derived and normal platelets, studied with anti-fibronectin antibodies, were similar. Furthermore, 125I-labeled protein A binds to anti-fibronectin-treated platelets from the two diseases investigated in the same fashion as in normal controls. No role for plasma fibronectin was detected in platelet aggregation induced by ADP, thrombin, collagen, epinephrine, and arachidonic acid. Thus our results do not indicate a direct quantitative role of fibronectin in the adhesion anomalies encountered in these diseases. However, fibronectin may still be important to platelet adhesion and normal hemostasis processes through interactions with the plasma von Willebrand factor and the membrane glycoproteins IIb and III, which have been shown to be deficient in von Willebrand's disease and thrombasthenia, respectively.

Blood Platelets↗