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Biomedical subjects

J Vermylen

Publications and source records attributed to J Vermylen.

At least 127 records · Page 7Linked to original sources
PubMed1993

Incidence of inhibitor development in a group of young hemophilia A patients treated exclusively with lyophilized cryoprecipitate.

The incidence of neutralizing isoantibody formation to infused factor VIII in a cohort of 67 hemophilia A patients, born between January 1, 1971 and April 30, 1990, who had been treated exclusively with lyophilized cryoprecipitate, was 6% (5.3 per 1,000 patient years of observation). The age-dependent cumulative risk was 4.6% at 4 years of age and 6.7% at 8 years of age. Recent reports in patients treated with a variety of more pure concentrates show a much higher incidence of inhibitor formation and tend to be used as a reference when new concentrates are introduced. We believe that a patient group, such as the one studied here, is a more suitable reference population because these patients have been exclusively treated with a single factor VIII preparation.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Human platelet aggregation by murine monoclonal antiplatelet antibodies is subtype-dependent.

Twenty murine monoclonal antibodies (MoAbs) generated against different human platelet antigens induced clumping of human platelets in plasma and buffer. Whereas one MoAb could agglutinate platelets, clumping for 19 MoAbs was blocked by metabolic inhibitors, indicating that these induce platelet activation. Fifteen MoAbs were of IgG1, two of IgG2a, and two of IgG2b subtype. F(ab')2 fragments of these did not evoke an aggregatory response, but specifically inhibited aggregations by and binding of their respective intact MoAbs to platelets. Single-platelet counting technology indicated that the MoAbs bind through their antigen-binding and Fc domains mainly to the surface of the same platelet, rather than cause interplatelet-binding. Despite these similarities, the mechanism of action was nevertheless subtype-dependent. Aggregation induced by all IgG1 antibodies could consistently be prevented by blocking the Fc gamma II-receptor, whereas aggregations induced by all IgG2 antibodies still occurred with blocked Fc-receptor, provided functional complement was present. We therefore conclude that platelet activation by MoAb-binding is initiated by antigen recognition followed by an Fc domain-dependent step, which involves the Fc gamma II-receptor for IgG1-type MoAbs and complement-binding for IgG2-type MoAbs. Thus, antibodies of different subtypes can aggregate platelets via different pathways.

Animals↗
PubMed1993

A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurized factor VIII concentrate.

In May 1990, 218 patients with haemophilia A regularly attending the Leuven Haemophilia Center were randomly assigned to a group receiving either of two newly introduced factor VIII concentrates: factor VIII-P, an intermediate purity pasteurized concentrate, or factor VIII-SD, a high purity concentrate treated with solvent-detergent for viral inactivation. Patients were followed from May 1990 until October 1991. Between August 1991 and October 1991 a clinically important factor VIII inhibitor was detected in five out of the 109 patients receiving factor VIII-P while none of the 109 patients receiving factor VIII-SD developed such antibodies. All patients acquiring an inhibitor had previously been clinically tolerant to transfused factor VIII with 200 to more than 1,000 days of exposure to factor VIII prior to May 1990. Patients with inhibitors were transfused daily with 30 U factor VIII-SD per kg body weight, which was associated with a gradual decline of the inhibitor level. In all patients the antibodies were relatively slow-acting and predominantly directed towards the light chain of factor VIII. This study demonstrates a higher than expected incidence of factor VIII inhibitors associated with the use of a specific factor VIII concentrate in multitransfused haemophilia A patients. It indicates the usefulness of evaluating newly introduced concentrates in prospective, randomized trials.

Adolescent↗
PubMed1993

Increased thromboxane formation in diabetic pregnancy as a possible contributor to preeclampsia.

OBJECTIVE: Because pregnant women with diabetes have an increased risk of preeclampsia, we tested the hypothesis that urinary excretion of thromboxane metabolites is increased in diabetic pregnancies without evidence of preeclampsia at the time of testing. STUDY DESIGN: Urinary excretion of thromboxane A2 metabolites (either 2,3-dinor-thromboxane B2 or 11-dehydro-thromboxane B2) was measured in 24 type I pregnant diabetic individuals and in 20 women with normal pregnancies between 28 and 32 weeks' gestation. RESULTS: The amount of 2,3-dinor-thromboxane B2 and 11-dehydro-thromboxane B2 in the urine of pregnant women with diabetes (1727 +/- 415 and 827 +/- 276 pg/mg creatinine) was significantly higher than in women with normal pregnancies (638 +/- 218 and 178 +/- 145 pg/mg creatinine) (p < 0.002 and p < 0.001). CONCLUSION: Our findings support a role for thromboxane in the pathogenesis of preeclampsia.

Diabetes Mellitus, Type 1↗
PubMed1993

Nailfold capillaroscopy in connective tissue disorders and in Raynaud's phenomenon.

This article focuses on the value and the limitations of nailfold capillaroscopy in the differential diagnosis of certain connective tissue diseases and in the early recognition of secondary Raynaud's phenomenon. The finding of a "scleroderma-pattern" (apical enlargement and drop-out of capillaries) points almost certainly to an underlying progressive systemic sclerosis, mixed connective tissue disease or dermatomyositis.

Arthritis, Rheumatoid↗
PubMed1993

MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man.

BACKGROUND: Fibrinogen-dependent cross-linking of glycoprotein (GP) IIb/IIIa on activated platelets is the final mechanism leading to platelet aggregation. Inhibition of this mechanism may result in a novel antithrombotic agent. We studied the activity of MK-383 (L-700,462), a new, nonpeptide GPIIb/IIIa antagonist, in vitro and in vivo, in man. METHODS AND RESULTS: MK-383, a nonpeptide tyrosine derivative, dose-dependently inhibited fibrinogen-dependent platelet aggregation, in vitro. Binding of 125I-labeled fibrinogen to activated platelets was prevented in a competitive manner with an IC50 of 10 +/- 4.2 nmol/L. The activity and tolerability of MK-383 were evaluated in a two-part double-blind, placebo-controlled, dose-escalation study in healthy male subjects using 1- and 4-hour intravenous infusions. Effects on ADP- and collagen-induced ex vivo platelet aggregation (APA or CPA) and template bleeding time (TBT) were evaluated. Twenty-four subjects participated in the 1-hour part. Six received placebo and 18 MK-383 in doses ranging from 0.05 to 0.40 microgram.kg-1 x min-1. MK-383 inhibited platelet aggregation and prolonged bleeding time in a dose-dependent manner. APA and CPA were totally inhibited at the end of infusion of 0.4 microgram.kg-1 x min-1 and returned to 55% and 89% of baseline, respectively, at 3 hours after infusion. TBT was prolonged at this dose from 5.0 +/- 1.3 minutes predose to 22.7 +/- 6 minutes at the end of the infusion (P < .01) and was normalized by 3 hours after infusion. In the 4-hour infusion part, 15 subjects received MK-383 (0.1 to 0.2 microgram.kg-1 x min-1), and five received placebo. Complete inhibition of ex vivo platelet aggregation was seen at 0.15 and 0.2 microgram.kg-1 x min-1. At 0.2 microgram.kg-1 x min-1, TBT was prolonged from 4.4 +/- 1.2 to 23.9 +/- 4.3 minutes at the end of infusion (P < .01) and remained slightly prolonged 3 hours after infusion (7.2 +/- 1.8 minutes). No adverse effects were observed in any of the 33 subjects receiving MK-383. CONCLUSIONS: The results from this study indicate that MK-383 appears to be well tolerated and active in man. It is the first nonpeptide GPIIb/IIIa antagonist that can be used to investigate the antithrombotic potential of this new class of antiplatelet agents.

Bleeding Time↗
PubMed1993

A monoclonal antibody recognizes a von Willebrand factor domain within the amino-terminal portion of the subunit that modulates the function of the glycoprotein IB- and IIB/IIIA-binding domains.

We developed a monoclonal antibody, 1C1E7, against vWf that increases ristocetin-induced platelet aggregation in a dose-dependent manner and lowers the threshold concentration of ristocetin needed to obtain a full aggregatory response. The platelet aggregatory effect of asialo vWf (ASvWf) also is enhanced by 1C1E7, in the presence or absence of glycoprotein (GP) IIb/IIIa receptor antagonism. In the presence of ristocetin, both intact 1C1E7 and its Fab fragments enhance specific binding of 125I-vWf to platelets. With 1C1E7, the intermediate and higher molecular weight multimers of vWf are preferentially bound to both GP Ib and GP IIb/IIIa. Thrombin-induced 125I-vWf binding to GP IIb/IIIa also is increased by 1C1E7. Maximal binding of 1C1E7 to vWf corresponds to 0.97 mol/mol vWf monomer with a Kd of 4.7 x 10(-10) M. 1C1E7 reacts with a 34/36-kD tryptic fragment (III-T4) and a 34-kD plasmic fragment (P34), which localizes the epitope between amino acid residues 1 and 272; this was confirmed by NH2-terminal amino acid sequencing. Finally, platelet aggregation by ASvWf was associated with a sharp rise in intracellular Ca2+ only in the presence of 1C1E7. An antibody-mediated conformational change of vWf may result in an improved presentation of the GP Ib- and GP IIb/IIIa-binding domains of mainly the larger multimers; the increased density of vWf on the platelet surface leads to platelet activation. The antibody may thus recognize a domain of relevance for vWf physiology.

Amino Acid Sequence↗
PubMed1992

Cell surface heparan sulfate proteoglycans from human vascular endothelial cells. Core protein characterization and antithrombin III binding properties.

Human aortic endothelial cells (HAEC) and human umbilical vein endothelial cells (HUVEC) were labeled with 35SO(4)2- for 48 h. The membrane-associated proteoglycans were solubilized from these monolayers with detergent and purified by ion-exchange chromatography on Mono Q, incorporation in liposomes, and gel filtration. The liposome-intercalated proteoglycans were 125I-iodinated and treated with heparitinase before SDS-polyacrylamide gel electrophoresis. Radio-labeled proteins with apparent molecular masses of 130, 60, 46, 35, and 30 kDa (HAEC) and 180, 130, 62, 43, and 35 kDa (HUVEC) were detected by autoradiography. Further characterization by affinity chromatography on immobilized monoclonal antibodies and by Northern blot analysis provided evidence for the expression of syndecan, glypican, and fibroglycan in human endothelial cells. Most of the heparan sulfate which accumulated in the subendothelial matrix was implanted on a 400-kDa core protein. This protein was immunologically related to perlecan and bound to fibronectin. Binding studies on immobilized antithrombin III suggested that all membrane-associated heparan sulfate proteoglycan forms had the capacity to bind to antithrombin III but that high affinity binding was more typical for glypican. Most of the proteoglycans isolated from the extracellular matrix also bound only with low affinity to antithrombin III. These results imply that glypican may specifically contribute to the antithrombotic properties of the vascular wall.

Antithrombin III↗
PubMed1992

Disturbed platelet aggregation to collagen associated with an antibody against an 85- to 90-Kd platelet glycoprotein in a patient with prolonged bleeding time.

We studied a 5-year-old girl presenting with a markedly prolonged bleeding time. Her platelets were refractory to collagen stimulation, but the response to other agonists was normal. There were no coagulation abnormalities as measured by standard tests. Two-dimensional electrophoresis showed no abnormalities of the patient's platelet membrane glycoproteins. When the patient's plasma or purified plasma IgG was mixed with normal platelets, collagen-induced platelet aggregation was blocked. Western blotting showed the presence of an antibody in the patient's plasma directed against a protein of molecular weight 85 to 90 Kd under both reducing and nonreducing conditions. This protein comigrated with glycoprotein (GP) IV immunoprecipitated by OKM5 from 125I-labeled platelets. Immunoprecipitation of 125I-labeled normal platelet glycoproteins with the patient's IgGs also yielded an 85- to 90-Kd protein that migrated on the diagonal following nonreduced/reduced two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Despite similarities in electrophoretic behavior, the antigen was not demonstrated to be GPIV, since purified GPIV was not recognized by the antibody.

Antibodies↗
PubMed1992

Thromboxane synthase inhibitors and receptor antagonists.

Platelet activation plays a major role in myocardial infarction and in reocclusion following successful thrombolysis, as corroborated by several clinical studies using aspirin. However, the overall reduction of new vascular complications in patients with symptomatic arterial disease by aspirin was only around 25%. Therefore, there is great interest in finding new means to inhibit platelet activation more efficiently. One line of research has focused on ways to interfere with the action of thromboxane A2 in a more selective way than aspirin does. As such, the development of thromboxane synthase inhibitors, followed by thromboxane receptor antagonists, raised hopes for a better treatment. However, both classes of drugs have some drawbacks, which could be overcome by combining them. This aim has led to the development of compounds that intrinsically possess both activities. Ongoing research indicates that such a dual inhibitor may indeed be more powerful than either aspirin or drugs with the single actions.

Aspirin↗
PubMed1992

HIV-related thrombocytopenia.

HIV-related chronic ITP is caused by an accelerated platelet destruction due to adsorption of circulating immune complexes and to specific anti-platelet antibodies, but perhaps also by a defective thrombopoiesis resulting from invasion of the megakaryocytes by the retrovirus. Treatment is needed when platelet numbers drop beneath 20.10(9)/L or when severe bleeding symptoms occur. Steroids, commercially available immunoglobulins for IV use, AZT and anti-Rh immunoglobulins can be administered, although relapses are frequent after withdrawal of the drugs. Recurrences after splenectomy are far less common, but the progression towards AIDS might be accelerated.

Antigen-Antibody Complex↗
PubMed1992

Are antiphospholipid antibodies clinically relevant in dialysis patients?

A cohort of 60 stable dialysis patients (56 haemodialysis, 4 continuous ambulatory peritoneal dialysis) was followed for 1 year to determine the relationship between anticardiolipin (aCL) antibodies and lupus anticoagulant (LA), and clinical events. The outcome measures were death, arterial, venous, and fistula thromboses, and fistula repairs. At baseline 15% had antibodies (5/60 IgG aCL, 3/60 LA, and 1/60 had both); 15 patients had a history of arterial thrombosis (1 patient was aCL positive), seven venous thrombosis (1 patient LA positive), 10 fistula thromboses (1 aCL positive); and 21 had a history of fistula repairs (4 aCL positive). Renal diagnosis, age (66.78 versus 59.67 years) and duration of dialysis (38.11 versus 45.25 months) were similar in patients with and without aCL antibodies or LA. Only the sex ratio showed a female predominance in the aCL- or LA-positive patients compared to the negative patients (3M:6F versus 36M:15F), but this was not significant (P = 0.07). After 1 year there were 10 deaths (1 LA positive), 12 thrombotic events in eight patients (none aCL or LA positive), and nine fistula repairs in seven patients (1 aCL-positive patient). We are unable to show higher rates of death, thrombotic event, or fistula repair in dialysis patients with aCL antibodies or LA followed up for 1 year in one centre. The clinical importance of antiphospholipid antibodies in dialysis patients is uncertain.

Adult↗
PubMed1992

A new lupus anticoagulant neutralization test based on platelet-derived vesicles.

We here present an easily standardizable and reproducible procedure which clearly separates lupus anticoagulants (LA) from coagulation factor inhibitors. This new LA neutralization test makes use of platelet-derived microvesicles which were prepared as follows: gel-filtered platelets (4 x 10(5)/microliters) were incubated with 60 microM of the calcium ionophore A23187 for 20 min at 37 degrees C. The vesicles were separated from the platelet aggregates by centrifugation at 1000 g for 10 min. The vesicle containing supernatant was then spun down at 15,000 g for 15 min, lyophilized and stored at -20 degrees C until used. The vesicles were resuspended in plasma from normal individuals, from patients with LA activity, from patients with factor VIII inhibitors, from patients with congenital factor deficiencies and from patients receiving oral anticoagulants or intravenous heparin. A kaolin clotting time was performed in the absence (KCT) or presence of these vesicles (KCTves) and the ratios of these times to their respective mean normal times were calculated. Segregation of LA patients from all remaining patients except heparinized ones could be made with a high degree of accuracy. A thrombin time was needed to separate LA from heparinized patients. The method was highly reproducible and only minor (negligible) differences in potencies were observed between different vesicle preparations. Both the intra-batch and the inter-batch coefficients of variations on the KCTves were lower than 6%.

Blood Coagulation Factors↗
PubMed1992

A patient with von Willebrand's disease characterized by a compound heterozygosity for a substitution of Arg854 by Gln in the putative factor-VIII-binding domain of von Willebrand factor (vWF) on one allele and very low levels of mRNA from the second vWF allele.

We describe a patient with a lifelong bleeding disorder previously classified as von Willebrand's disease (vWD) type I. The factor VIII (FVIII) level in this patient was disproportionately low and we showed that this was due to a decreased factor VIII binding capacity of her vWF. To characterize the molecular defect in this type of vWD, a cDNA-dependent polymerase chain reaction (PCR) amplification was performed using platelet RNA as a template. Direct sequencing of the amplified fragment, which encodes for the FVIII-binding domain, showed a single nucleotide change in exon 20 at codon 854, resulting in the substitution of CAG glutamine (Gln) for CGG arginine (Arg). At the level of the cDNA only the mutated sequence was found, whereas at genomic DNA level the patient was heterozygous for this mutation. This patient is therefore a compound heterozygote for a point mutation resulting in a FVIII-binding defect and a vWF allele with low transcript levels.

Adult↗
PubMed1992

Influence of anticoagulation on blood loss following dental extractions.

The coagulation activity level at which oral surgery procedures can be performed in anticoagulated patients without triggering bleeding complications and without enhancing the risk of developing thrombo-embolic events remains controversial. The objective of the present study was to evaluate blood loss following dental extractions at different levels of anticoagulation and to determine its effect on wound closure rates. Blood loss was measured following the removal of four front teeth in warfarinized rabbits. Immediate blood loss was evaluated by determining the tooth socket bleeding times and by using a technique based on hemoglobin determinations. Long-term blood loss was assessed by comparison of labeled red-blood-cell disappearance curves. The results showed that blood loss following dental extractions was significantly greater in animals anticoagulated at a therapeutic level than in non-anticoagulated control animals. Determination of blood loss at different levels of anticoagulation clearly demonstrated that complete correction of the coagulation activity was unnecessary. Partial correction (INR values of 1.6-1.8) allowed extractions to be performed without extensive blood loss. With this technique of partial correction, the period of interruption of the anticoagulation could be kept very short, and the risk of postoperative bleeding complications was minimal. Wound closure rates were negatively influenced in anticoagulated animals.

Analysis of Variance↗