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U Seligsohn

Publications and source records attributed to U Seligsohn.

At least 19 recordsLinked to original sources
PubMed1992

Characterization of three mutations causing von Willebrand disease type IIA in five unrelated families.

Von Willebrand disease (vWD) type IIA is characterized by decreased ristocetin-induced platelet aggregation, and by the absence from plasma of high molecular weight multimers of von Willebrand factor (vWF). Most mutations causing vWD type IIA are clustered within the A2 domain of the mature vWF subunit that is encoded by exon 28. Using the polymerase chain reaction (PCR), the entire exon 28 from patients with vWD type IIA and normal controls was amplified and sequenced. Three missense mutations were detected that result in the amino acid substitutions were detected that result in the amino acid substitutions Arg(834)----Trp, Gly(742)----Glu, and Ser(743)----Leu. The first mutation occurred independently in three unrelated families; each of the latter mutations was found in one family. By restriction endonuclease analysis and allele-specific oligonucleotide (ASO) hybridization the mutations were confirmed in affected family members and excluded in unaffected members and 50 normal controls. The apparently high frequency of identical independent mutations among patients with vWD type IIA suggests that a precise diagnosis may be possible in a majority of patients using relatively simple recombinant DNA screening assays.

Alleles↗
PubMed1992

The effect of the plasma levels of proteins C and S on the prediction of warfarin maintenance dose requirements.

OBJECTIVE: Determination of the effects of the vitamin K-dependent anticoagulants, proteins C and S, on warfarin dose requirements and on the prediction error of a bayesian warfarin dose predicting program. METHODS: Patients in the study were consecutive inpatients (n = 18) starting treatment with warfarin who were monitored as outpatients for 4 weeks. The following measurements were taken: repeated (n = 8) prothrombin times, expressed as the international normalized ratio (INR), plasma protein C and S antigen levels (percentage of pooled normal plasma), demographic, clinical and biochemical variables. RESULTS: Maintenance doses (adjusted to INR 2.5) were 6.7 +/- 3.4 mg/day. Protein C decreased to 56.9% +/- 15.3%, protein S to 63.7% +/- 17.3%, INR increased to 2.46 +/- 0.14. Prediction error decreased from 2.84 +/- 2.0 mg/day to 0.95 +/- 0.78 mg/day. Protein C accounted for only 4.2% of the mean maintenance dose but protein C and S levels accounted for 31% of the mean dose prediction error. CONCLUSION: Protein C and S levels affect warfarin doses and predictions significantly but not to a clinically meaningful degree.

Adolescent↗
PubMed1992

The inheritance of type I and type III von Willebrand's disease in Israel: linkage analysis, carrier detection and prenatal diagnosis using three intragenic restriction fragment length polymorphisms.

Three intragenic restriction fragment length polymorphisms (RFLPs) were used to study linkage and analyse the mode of inheritance in type I and type III von Willebrand's disease (vWD). In two families linkage was established between Sac I RFLPs and the inheritance of type I vWD. RFLP analysis of amniocyte DNA from a potentially affected foetus enabled us to establish a prenatal diagnosis of vWD in a third family with type I vWD. Linkage was also established in four families between the Sac I and two Taq I RFLPs and the inheritance of type III vWD. All type III probands were homozygotes and inherited the same mutant vWF allele from both parents. Heterozygous carriers from one type III family were phenotypically normal and could be detected only by linkage analysis, whereas carriers from the remaining three type III families were asymptomatic but had decreased values of vWF antigen and activity. RFLP-based linkage analysis of vWD alleles provides a way to improve the diagnostic precision, detect carriers, and may be useful for prenatal diagnosis of type III vWD.

Female↗
PubMed1992

Dental surgery in patients with severe factor XI deficiency without plasma replacement.

Bleeding following dental extraction is frequently the first manifestation of severe factor XI deficiency. Safe oral surgery has previously been performed in such patients by using plasma replacement therapy with or without concomitant administration of antifibrinolytic agents. The aim of this study was to determine whether such patients can undergo safe dental extractions using only an antifibrinolytic agent. The study group consisted of 19 patients with severe factor XI deficiency (factor XI:C level less than 14 U/dl) who had previously bled following dental extractions (14 patients) or other trauma (five patients). Tranexamic acid, 1 g q.i.d., was given from 12 h before surgery, until 7 days afterwards. No excessive bleeding was observed following dental extractions. One patient had slight oozing after 3 days which ceased spontaneously. Thus, plasma replacement no longer appears necessary for patients with severe factor XI deficiency requiring dental extractions.

Adult↗
PubMed1991

Platelet fibrinogen and vitronectin in Glanzmann thrombasthenia: evidence consistent with specific roles for glycoprotein IIb/IIIA and alpha v beta 3 integrins in platelet protein trafficking.

To assess the individual contributions of the platelet glycoprotein (GP) IIb/IIIa receptor and the alpha v beta 3 vitronectin receptor to platelet levels of fibrinogen and vitronectin, we analyzed the platelets from two groups of Glanzmann thrombasthenic patients: Iraqi-Jews, whose platelets lack both receptors, and Arab patients in Israel, whose platelets lack GPIIb/IIIa, but have normal or increased numbers of alpha v beta 3 vitronectin receptors. The platelets from both thrombasthenic groups had profound deficiencies of fibrinogen, but the defect in the Iraqi-Jewish patients' platelets appeared to be slightly more severe. This finding indicates that GPIIb/IIIa is the major determinant of platelet fibrinogen, presumably acting by receptor-mediated uptake, and that the alpha v beta 3 vitronectin receptor plays little or no role. Arab patients' platelets have normal amounts of platelet vitronectin, whereas Iraqi-Jewish patients' platelets have nearly five times as much vitronectin as control or Arab patients' platelets. To account for these data, we propose a working hypothesis in which vitronectin is synthesized in megakaryocytes and the alpha v beta 3 vitronectin receptor is involved in transport of the protein out of megakaryocytes and/or platelets. Collectively, these observations suggest that in addition to their recognized roles in cell adhesion and in the interaction of cells with extracellular proteins, integrin receptors may be important in protein trafficking into, and perhaps out of, platelets.

Blood Platelets↗
PubMed1991

Detection of the Glanzmann's thrombasthenia mutations in Arab and Iraqi-Jewish patients by polymerase chain reaction and restriction analysis of blood or urine samples.

Severe Glanzmann's thrombasthenia is relatively frequent in Iraqi-Jews and Arabs residing in Israel. We have recently described the mutations responsible for the disease in Iraqi-Jews--an 11 base pair deletion in exon 12 of the glycoprotein IIIa gene, and in Arabs--a 13 base pair deletion at the AG acceptor splice site of exon 4 on the glycoprotein IIb gene. In this communication we show that the Iraqi-Jewish mutation can be identified directly by polymerase chain reaction and gel electrophoresis. With specially designed oligonucleotide primers encompassing the mutation site, an 80 base pair segment amplified in healthy controls was clearly distinguished from the 69 base pair segment produced in patients. Patients from 11 unrelated Iraqi-Jewish families had the same mutation. The Arab mutation was identified by first amplifying a DNA segment consisting of 312 base pairs in controls and of 299 base pairs in patients, and then digestion by a restriction enzyme Stu-1, which recognizes a site that is absent in the mutant gene. In controls the 312 bp segment was digested into 235 and 77 bp fragments, while in patients there was no change in the size of the amplified 299 bp segment. The mutation was found in patients from 3 out of 5 unrelated Arab families. Both Iraqi-Jewish and Arab mutations were detectable in DNA extracted from blood and urine samples. The described simple methods of identifying the mutations should be useful for detection of the numerous potential carriers among the affected kindreds and for prenatal diagnosis using DNA extracted from chorionic villi samples.

Base Sequence↗
PubMed1991

Factor XI deficiency in Ashkenazi Jews in Israel.

BACKGROUND AND METHODS: Severe factor XI deficiency, which is relatively common among Ashkenazi Jews, is associated with injury-related bleeding of considerable severity. Three point mutations--a splice-junction abnormality (Type I), Glu117----Stop (Type II), and Phe283----Leu (Type III)--have been described in six patients with factor XI deficiency. Clinical correlations with these mutations have not been carried out. We determined the relative frequency of the mutations and their association with plasma levels of factor XI clotting activity and bleeding, analyzing the mutations with the polymerase chain reaction and restriction-enzyme digestion. RESULTS: The Type II and Type III mutations had similar frequencies among 43 Ashkenazi Jewish probands with severe factor XI deficiency; these two mutations accounted for 49 percent and 47 percent, respectively, of a total of 86 analyzed alleles. Among 40 of the probands and 12 of their relatives with severe factor XI deficiency, patients homozygous for Type III mutation had a significantly higher level of factor XI clotting activity (mean [+/- SD] percentage of normal values, 9.7 +/- 3.8 percent; n = 13) than those homozygous for Type II mutation (1.2 +/- 0.5 percent, n = 16) or compound heterozygotes with Type II/III mutation (3.3 +/- 1.6 percent, n = 23), as well as significantly fewer episodes of injury-related bleeding. Each of these three groups had a similarly increased proportion of episodes of bleeding complications after surgery at sites with enhanced local fibrinolysis, such as the urinary tract, or during tooth extraction. CONCLUSIONS: Type II and Type III mutations are the predominant causes of factor XI deficiency among Ashkenazi Jews. Genotypic analysis, assay for factor XI, and consideration of the type and location of surgery can be helpful in planning operations in patients with this disorder.

Alleles↗
PubMed1991

The molecular genetic basis of Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in Israel.

Glanzmann thrombasthenia is an autosomal recessive bleeding disorder characterized by a decrease or absence of functional platelet glycoprotein (GP) IIb-IIIa (alpha IIb beta 3) integrin receptors. Although thrombasthenia is a rare disorder, its occurrence is increased in some regions of the world where intracommunity marriage and consanguinity are commonplace, resulting in increased expression of autosomal recessive traits. We have been studying two populations having an unusually high frequency of Glanzmann disease, Iraqi Jews and Arabs living in Israel, and were able to distinguish the populations on the basis of immunodetectable GPIIIa and platelet surface vitronectin receptor (alpha v beta 3) expression. In this article, we describe molecular genetic studies based on use of the PCR that have allowed us to characterize platelet mRNA sequences encoding GPIIb and GPIIIa from patients in these populations. In six of six Iraqi-Jewish families studied, cDNA sequence analysis identified an 11-base deletion within exon 12 of the GPIIIa gene. This mutation produces a frameshift leading to protein termination shortly before the transmembrane domain of GPIIIa. In contrast, a 13-base deletion encompassing the splice acceptor site of exon 4 of the GPIIb gene was found in three of five Arab kindreds studied. This deletion results in forced alternative splicing to a downstream AG acceptor, producing a 6-amino acid deletion in the GPIIb protein, including a single cysteine residue. These nucleotide sequence variations were exploited to design a rapid, PCR-based oligonucleotide dot-blot hybridization test for both pre- and postnatal diagnosis of Glanzmann disease. These studies demonstrate the heterogeneity of Glanzmann thrombasthenia in different populations, and its homogeneity within geographically restricted populations, and offer insight into the requirements for integrin surface expression.

Base Sequence↗
PubMed1991

Platelet vitronectin receptor expression differentiates Iraqi-Jewish from Arab patients with Glanzmann thrombasthenia in Israel.

Glanzmann thrombasthenia is a rare, inherited disorder of the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) complex. We previously identified two distinct populations with this disorder in Israel, Iraqi-Jews and Arabs. The groups are indistinguishable in hemorrhagic symptoms and platelet GP IIB/IIIa receptor deficiency, but they differ in their platelet immunodetectable GP IIIa (beta 3), with the Iraqi-Jewish population expressing no detectable GP IIIa and the Arab population expressing small amounts. We have now examined the platelets of these two populations as well as normal platelets for the alpha v beta 3 vitronectin receptor. Normal platelets contained between approximately 50 to 100 alpha v beta 3 vitronectin receptors as judged by the binding of antibodies to both alpha v (LM142) and the intact alpha v beta 3 vitronectin receptor complex (LM609). In addition, normal platelets bound to immobilized vitronectin in the presence of 1 mmol/LMnCl2; the adhesion was mediated predominantly through GP IIb/IIIa, but with a distinct contribution by the alpha v beta 3 vitronectin receptor, as determined by monoclonal antibody inhibition studies. Iraqi-Jewish patients' platelets had a profound decrease in immunodetectable alpha v beta 3 vitronectin receptors, and their platelets did not adhere well to vitronectin. In contrast, Arab patients' platelets had normal or increased numbers of platelet alpha v beta 3 vitronectin receptors, and these receptors functioned well in the vitronectin adhesion assay, taking over much of the adhesion mediated by GP IIb/IIIa in normal platelets. These studies define further the heterogeneity of the molecular basis of Glanzmann thrombasthenia; they also have more widespread implications for understanding the synthesis and function of the beta 3 family of integrin receptors.

Blood Platelets↗
PubMed1990

Repeat infusion of recombinant tissue-type plasminogen activator in patients with acute myocardial infarction and early recurrent myocardial ischemia.

When conventional treatment of patients with early clinical reinfarction after thrombolytic therapy fails, mechanical revascularization may be attempted. An alternative strategy, repeat thrombolytic infusions, is reported. Fifty-two patients with acute myocardial infarction were treated with one or two additional thrombolytic infusions of recombinant tissue-type plasminogen activator (rt-PA) because of nonsustained ischemia after initial treatment with rt-PA or streptokinase. Thirty-five patients received the second infusion within 1 h of the first; 13 patients received the second infusion 1 to 72 h after the first and 4 patients received it later during their hospitalization. Bleeding complications occurred in 10 patients (19%); however, most of these were minor (no intracranial bleeding) and only 2 patients required blood transfusion. In 14 patients in whom the decrease in fibrinogen and plasminogen levels was measured after the first and second infusions, this decrease was only 25% and 63%, respectively--only slightly higher than the 22% and 53% decreases measured in 63 patients who had only one rt-PA infusion. In 44 patients (85%), the acute ischemia resolved completely within 1 h after initiation of the second infusion. In 23 patients (44%), pain and ST segment elevation did not recur and invasive coronary intervention was avoided. Thus, repeat rt-PA infusions can stabilize a substantial number of patients with acute reinfarction and, even when relief is temporary, repeat rt-PA infusions can minimize myocardial damage while patients await mechanical revascularization.

Female↗
PubMed1990

Hereditary deficiency of all vitamin K-dependent procoagulants and anticoagulants.

Hereditary combined deficiency of vitamin K-dependent factors is a rare entity. We report a 7-year-old girl of Arab origin with hereditary deficiency of the procoagulants factors II, VII, IX and X and the natural anticoagulants proteins C and S. The patient is the tenth offspring of a consanguinous marriage and presented at 6 weeks with spontaneous intracerebral haemorrhage. Symptoms improved following plasma infusion. A sibling died at 5 d from uncontrollable umbilical bleeding. Blood coagulation work-up at 6 years showed: factor II:C (activity) 12 U/dl, factor II:Ag (antigen) 40 U/dl; factor VII:C 12 U/dl; factor IX:C 36 U/dl, factor IX:Ag 57 U/dl; factor X:C 17 U/dl, factor X:Ag 54 U/dl; protein C activity 43 U/dl; protein C:Ag 45 U/dl; protein S:Ag 34 U/dl; levels of factors V:C and VIII:C were normal. Assays of coagulation factors in the parents and five of the siblings were within the normal range. Following acute infection and dilantin therapy procoagulant activity levels were reduced further and were partially increased after vitamin K infusion. Crossed immunoelectrophoresis of prothrombin in the presence of calcium lactate revealed a population of des-carboxyprothrombin. Serum vitamin K epoxide levels were undetectable. The data suggest that the defect in our patient stems from abnormal carboxylation of the vitamin K-dependent proteins and that the mode of inheritance is autosomal recessive.

Blood Coagulation Disorders↗
PubMed1990

Rapid resolution of ST elevation and prediction of clinical outcome in patients undergoing thrombolysis with alteplase (recombinant tissue-type plasminogen activator): results of the Israeli Study of Early Intervention in Myocardial Infarction.

Alteplase (recombinant tissue-type plasminogen activator (rt-PA)) was infused within four hours of onset of symptoms in 286 patients with acute myocardial infarction. Delayed coronary angiography was performed 72 hours after admission with coronary angioplasty if indicated. Electrocardiographic monitoring was continuous during the first hour of treatment. The sum of the ST segment elevations (sigma ST) was calculated on electrocardiograms recorded at entry and an hour later. ST elevations resolved rapidly within one hour of treatment in 189 patients and persisted in 97 patients. Rapid resolution of ST elevation correlated with angiographic coronary patency as determined by coronary angiography 72 hours after admission. The patients with rapid resolution of sigma ST had significantly smaller infarcts and a better clinical outcome than the patients with persistent ST elevation. sigma ST values at entry and one hour after treatment had no additional independent predictive value. Rapid resolution of ST elevations in patients undergoing thrombolysis with alteplase was associated with a significantly smaller release of creatine kinase, better preservation of left ventricular function, lower morbidity, and less short and long term mortality. Rapid resolution of sigma ST elevation is an efficient indicator of clinical outcome in groups of patients with acute myocardial infarction undergoing thrombolysis with alteplase.

Aged↗
PubMed1990

Association of von Willebrand's disease with plasma cell dyscrasia and gastrointestinal angiodysplasia.

A patient with acquired von Willebrand's disease (type I) had both plasma cell dyscrasia and angiodysplasia of the intestine. Based on examination of the components of F VIII/von Willebrand's factor (VWF) and the results obtained following the administration of cryoprecipitate and DDAVP (1-desamino-8-D-arginine-vasopressin), it was suggested that the production and release of VIII/VWF was normal and the rapid disappearance from the circulation was related to adsorption by abnormal cells in the bone marrow. The relation of acquired von Willebrand's disease, plasma cell dyscrasia and angiodysplasia is discussed and the literature reviewed. Our patient is added to three previous reported cases of such an association of these three disorders.

Blood Vessels↗
PubMed1989

Correlation of baseline plasminogen activator inhibitor activity with patency of the infarct artery after thrombolytic therapy in acute myocardial infarction.

Increased levels of plasminogen activator inhibitor (PAI) have recently been described in patients with acute myocardial infarction (AMI). To correlate PAI levels to patency of infarct arteries after thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA), 125 consecutive patients with AMI were examined. Blood levels of fibrinogen, plasminogen, tissue plasminogen activator (t-PA) and PAI were measured before treatment initiation, 10 minutes after completion of rt-PA infusion and 24 and 48 hours after treatment. Coronary angiography, performed in all patients 72 hours after beginning rt-PA infusion, revealed patent infarct arteries in 97 patients and occluded infarct arteries in 28 patients. Pretreatment levels of PAI were significantly higher in patients with occluded infarct arteries (18.0 +/- 11.5 vs 10.5 +/- 9.3 IU/ml, p less than 0.01). Conceivably, higher levels of PAI may interfere with the natural thrombolytic process and make pharmacologic thrombolytic intervention less effective.

Arteries↗
PubMed1989

von Willebrand factor multimer patterns in pregnancy-induced hypertension.

Microangiopathy and disseminated platelet aggregation have been reported in thrombotic thrombocytopenic purpura (TTP) and pregnancy-induced hypertension (PIH). Since unusually large von Willebrand factor (vWF) multimers have been implicated in the evolvement of TTP, we analyzed factor VIII/vWF parameters in patients with PIH. Mean vWF: Ag level was significantly higher in 27 patients with PIH as compared to 20 matched healthy pregnant women (358 +/- 160 u/dl vs. 274 +/- 125 u/dl. p less than 0.05). Moreover, plasma vWF: Ag levels and the ratio of vWF: Ag to factor VIII were found to be linearly correlated to the severity of PIH. In contrast, no significant differences in mean levels of factor VIII and ristocetin cofactor were observed between these groups. Crossed immunoelectrophoresis of vWF revealed a higher incidence of a pre-peak and an increased migration index in the PIH group as compared to the control group (60% vs. 44% and 1.27 +/- 0.26 vs. 1.19 +/- 0.18, p less than 0.01 respectively). Analysis of plasma vWF multimer patterns by 1.4% agarose electrophoresis in 0.1% SDS revealed excessive amounts of large, medium and small size multimers in the PIH patients. Conceivably, the quantitative changes in vWF multimers reflect endothelial injury and may play a role in the microangiopathy observed in PIH.

Adult↗
PubMed1989

The relative frequency of hereditary thrombotic disorders among 107 patients with thrombophilia in Israel.

Since most patients with thrombophilia in Israel are referred for diagnosis to our center, it was possible to estimate the relative frequency of the hereditary disorders leading to thrombophilia. 107 unrelated patients were evaluated over 4 years. Diagnoses were established in 23 patients (21.5%) while in 84 (78.5%) no abnormality was detected. Antithrombin III deficiency was found in 8 patients (7.5%), dominant protein C deficiency in 6 (5.6%), recessive homozygous protein C deficiency in 1, protein S deficiency in 3 (2.8%) and dysfibrinogenemia in 1. Four additional patients (3.7%) had a lupus anticoagulant. The frequency of deep vein thrombosis and pulmonary embolism was similar in patients with and without a definite diagnosis. Thrombosis of visceral or cerebral vessels and a positive family history were more frequent among patients in whom a definite diagnosis was made. In both groups there was a substantial lag between the time of presentation of the first thrombotic episode and the time of evaluation. Since the number of referred patients with thrombophilia has gradually increased over the period of the study, it is at present impossible to establish the prevalence of the various hereditary disorders leading to thrombophilia in the population.

Adolescent↗
PubMed1989

Immunoblot analysis of platelet glycoprotein IIb in patients with Glanzmann thrombasthenia in Israel.

Recent studies have indicated that severe ('type I') Glanzmann thrombasthenia is a heterogeneous hereditary disorder caused by quantitative and/or qualitative abnormalities of platelet membrane glycoproteins (GP) IIb and IIIa. Immunoblot analysis of sodium dodecyl sulphate (SDS)-solubilized platelets was carried out on controls and 18 patients (12 Iraqi-Jews, two Iranian Jews and four Arabs) employing three antibodies (one monoclonal and two polyclonal) directed at different sites on GPIIb. Nonreduced control platelet samples contained a major Mr approximately 140k immunoreactive protein that was split into an Mr approximately 120k (alpha) and an Mr approximately 25k (beta) band after reduction with mercaptoethanol. The nonreduced samples from all 18 patients tested had trace amounts of Mr approximately 140k band corresponding to normal GPIIb; the intensity of this band was estimated to be less than 1% of the normal amount. Unlike the control samples, however, this Mr approximately 140k band did not change electrophoretic mobility following reduction. Since GPIIb originates from a single chain precursor molecule of Mr approximately 140k that comprises both the alpha and beta chains, and which does not change mobility with reduction, our data suggest that the platelets of these patients contain small amounts of this precursor.

Antibodies, Monoclonal↗