Drug-induced immune thrombocytopenia (DITP) is a serious complication of drug treatment. Previous studies demonstrated that most drug-dependent antibodies (DDAbs) react with the platelet membrane glycoprotein (GP) complexes IIb/IIIa and... more
Drug-induced immune thrombocytopenia (DITP) is a serious complication of drug treatment. Previous studies demonstrated that most drug-dependent antibodies (DDAbs) react with the platelet membrane glycoprotein (GP) complexes IIb/IIIa and Ib/IX/V. We analyzed the sera from 5 patients who presented with DITP after intake of carbimazole. Notably, thrombocytopenia induced by carbimazole was relatively mild in comparison to patients with DITP induced by quinidine. The sera reacted with platelets in an immunoassay on addition of the drug. In immunoprecipitation experiments with biotin-labeled platelets and endothelial cells, reactivity with the platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) could be demonstrated, whereas neither GPIIb/IIIa nor GPIb/IX was precipitated in the presence of the drug. These results could be confirmed by GP-specific immunoassay (MAIPA) using monoclonal antibodies (mabs) against PECAM-1. In addition, the binding of DDAbs could be abolished by prein...
Research Interests: Calcium, Cell Adhesion, Biological Sciences, Brain, Adaptive Immunity, and 15 moreChronic Disease, Animals, Blood, Clinical Sciences, CHEMICAL SCIENCES, Aged, Cardiovascular system, Amino Acid Sequence, Base Sequence, Adherens junctions, Cell Adhesion Molecules, Cell Membrane, Cell Aggregation, binding sites, and Cardiovascular medicine and haematology
A new platelet-specific alloantigen, termed Sita, was identified in a severe case of neonatal alloimmune thrombocytopenia. The Sita alloantigen is of low frequency (1/400) in the German population. Immunochemical studies demonstrated that... more
A new platelet-specific alloantigen, termed Sita, was identified in a severe case of neonatal alloimmune thrombocytopenia. The Sita alloantigen is of low frequency (1/400) in the German population. Immunochemical studies demonstrated that the Sita epitopes reside on platelet glycoprotein (GP) Ia. Nucleotide sequence analysis of GPIa cDNA derived from Sita-positive platelets showed C2531→T2531 point mutation, resulting in Thr799Met dimorphism. Analysis of genomic DNA from 22 Sita-negative normal individuals showed that the Thr799 is encoded by ACG2532 (90.9%) or ACA2532 (9.1%). To establish a DNA typing technique, we elucidated the organization of the GPIa gene adjacent to the polymorphic bases. The introns (421 bp and 1.2 kb) encompass a 142-bp exon with the 2 polymorphic bases 2531 and 2532. Polymerase chain reaction-restriction fragment length polymorphism analysis on DNA derived from 100 donors using the restriction enzyme MaeIII showed that the Met799 form of GPIa is restricted ...
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Background: Posttransfusion purpura (PTP) is characterized by severe thrombocytopenia and hemorrhagic diathesis about 1 week following blood transfusion. Only few studies exceed the description of single cases. Materials and methods:... more
Background: Posttransfusion purpura (PTP) is characterized by severe thrombocytopenia and hemorrhagic diathesis about 1 week following blood transfusion. Only few studies exceed the description of single cases. Materials and methods: Clinical data from 38 patients were analyzed. Platelet antibodies were studied by complement binding, immunofluorescence, MAIPA assay and acid elution techniques. Results: All patients were female. The mean age at onset was 60.7 years (35-78 years). 4 patients received whole blood, 28 were transfused with packed RBC. 11 of 13 patients (85%) had febrile, non hemolytic adverse reactions during the transfusion. The interval between transfusion and onset of purpura extended from 2 to 14 days, with a peak at 7 and 8 days. Hemorrhagic symptoms lasted 10.1 days. The minimal platelet count was 7.0 x 10(3)/microliters. The platelet count increased to over 50 x 10(3)/microliters after 13.9 days (n = 26), and to over 100 x 10(3)/microliters after 17.0 days (n = 22). 2 patients died of hemorrhagic complications. 24 patients were treated with glucocorticoids, 20 with intravenous immunoglobulins (ivIG), 17 of these received both therapies. 14 of 19 patients (74%) responded well to ivIG. In contrast, platelet transfusions produced no adequate increment, in 6 cases they provoked febrile reactions. 35 sera (92.1%) contained anti-Zwa, either alone or together with anti-HLA or in 1 case with anti-Bra. Anti-Baka and anti-Bakb were found in 1 case each. In 5 patients, anti-Zwa could be eluted from autologous Zwa-negative platelets. Conclusions: The broad clinical spectrum of PTP could be shown. Since 5% of the patients succumb to bleeding complications, the application of ivIG as therapy of choice is recommended. The phenomenon of elution of alloantibodies from autologous platelets is interpreted as a consequence of 'pseudo-specificity' which may play a role in the pathogenesis of PTP.
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... Wenn man eine Ko-horte Thrombozyten bei einem gesunden, normalen Individuum markiert,dann enthält diese Thrombozyten aller Altersstufen, die Elimination dieser Thrombozyten nimmt einen linearen Verlauf (. Abb. ... Diese Patienten... more
... Wenn man eine Ko-horte Thrombozyten bei einem gesunden, normalen Individuum markiert,dann enthält diese Thrombozyten aller Altersstufen, die Elimination dieser Thrombozyten nimmt einen linearen Verlauf (. Abb. ... Diese Patienten dürfen dann nur plasmaarme, evtl. ...
Alzheimer's disease (AD) is a complex, irreversible neurodegenerative disorder. At present there are neither reliable markers to diagnose AD at an early stage nor therapy. To investigate underlying disease mechanisms, induced... more
Alzheimer's disease (AD) is a complex, irreversible neurodegenerative disorder. At present there are neither reliable markers to diagnose AD at an early stage nor therapy. To investigate underlying disease mechanisms, induced pluripotent stem cells (iPSCs) allow the generation of patient-derived neuronal cells in a dish. In this study, employing iPS technology, we derived and characterized iPSCs from dermal fibroblasts of an 82-year-old female patient affected by sporadic AD. The AD-iPSCs were differentiated into neuronal cells, in order to generate disease-specific protein association networks modeling the molecular pathology on the transcriptome level of AD, to analyse the reflection of the disease phenotype in gene expression in AD-iPS neuronal cells, in particular in the ubiquitin-proteasome system (UPS), and to address expression of typical AD proteins. Our study demonstrates how an iPSC-based model system could represent (i) a tool to study the underlying molecular basis o...
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Heparin-induced thrombocytopenia (HIT) is a hypercoagulable syndrome strongly associated with thrombosis that is usually treated with drugs that inhibit factor Xa (danaparoid) or thrombin (lepirudin). In the present study the outcome of... more
Heparin-induced thrombocytopenia (HIT) is a hypercoagulable syndrome strongly associated with thrombosis that is usually treated with drugs that inhibit factor Xa (danaparoid) or thrombin (lepirudin). In the present study the outcome of HIT-patients treated with danaparoid or lepirudin was compared using the single or combined endpoints of new thromboembolic complications (new TECs), amputations and/or death, and major bleeding. HIT-patients treated with lepirudin were enrolled in two prospective trials and patients, who were identified in the same two laboratories during the same time period, who were not enrolled into these studies but treated with danaparoid, were assessed retrospectively according to a standardized questionnaire. 126 danaparoid (60.3% female) and 175 lepirudin treated patients (58.3% female) fulfilled the same inclusion and exclusion criteria. In a time-to-event-analysis the cumulative risk of combined endpoint was higher in HIT-patients without thromboembolic c...
Research Interests: Comparative Study, Platelet, Complication, Humans, Heparin, and 15 moreFemale, Male, Amputation, Incidence, Anticoagulants, Glycosaminoglycan, Clinical Sciences, Aged, Middle Aged, Questionnaires, Drug evaluation, Age Factors, Hemorrhage, Dermatan sulfate, and Cardiovascular medicine and haematology
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Platelet glycoprotein (GP) Ia is the major receptor for collagen and plays an important role in platelet adhesion and aggregation. Different gene polymorphisms have been identified that induce either various expression levels (C807T) or... more
Platelet glycoprotein (GP) Ia is the major receptor for collagen and plays an important role in platelet adhesion and aggregation. Different gene polymorphisms have been identified that induce either various expression levels (C807T) or alterations of the tertiary structure (A1648G) of GPIa. Previously, we could demonstrate an association of the GPIa C807T dimorphism with nonfatal myocardial infarction. We have now analysed the influence of the GPIa A1648G (Br, HPA-5) dimorphism on the risk of coronary artery disease (CAD) and acute myocardial infarction (AMI). DNA samples from 2163 male Caucasian patients who underwent coronary angiography were genotyped by polymerase chain reaction and restriction fragment length analysis. The relation of the GPIa A1648G dimorphism to the extent of CAD was determined by multiple regression analysis with adjustment for coronary risk factors. Odds ratios (OR) as an estimate of relative risk of CAD and AMI and two-tailed p-values were calculated by m...
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We recently described a new low-frequency platelet alloantigen on the human platelet glycoprotein (GP) Ib-IX complex, termed Iy(a), which was implicated in a severe case of neonatal alloimmune thrombocytopenia. Immunoprecipitation studies... more
We recently described a new low-frequency platelet alloantigen on the human platelet glycoprotein (GP) Ib-IX complex, termed Iy(a), which was implicated in a severe case of neonatal alloimmune thrombocytopenia. Immunoprecipitation studies with trypsin-treated platelets indicated that the Iy(a) alloantigenic determinants are formed by the membrane-associated remnant moiety of GP Ibalpha (GP Ibalpha(r)) together with GP Ibbeta and GP IX. To elucidate the molecular basis underlying the Iy(a) alloantigen, we amplified GPIbalpha(r), GPIbbeta, and GPIX genes by polymerase chain reaction (PCR). Nucleotide-sequence analysis of these 3 genes showed a G to A transition at position 141 on GPIbbeta gene in a subject positive for Iy(a). This transition resulted in a Gly(15)Glu dimorphism on the N-terminal domain of GPIbbeta. This finding was confirmed by genotyping analysis of 6 Iy(a)-positive subjects by restriction fragment length polymorphism (RFLP) studies using NarI endonuclease. In 300 ran...
Research Interests: Humans, Autoimmune diseases, Animals, Blood, Polymerase Chain Reaction, and 12 moreThrombocytopenia, Pedigree, Phenotype, Clinical Sciences, Newborn Infant, Amino Acid Substitution Rates, Epitopes, DNA mutational analysis, CHO cells, Cricetinae, Cardiovascular medicine and haematology, and Paediatrics and reproductive medicine
Recently, we have shown that two alleles of the glycoprotein (GP) Ia gene, designated C807 and T807, are associated with low or high platelet GPIa-IIa density and consequently with slower or faster rate of platelet adhesion to type I... more
Recently, we have shown that two alleles of the glycoprotein (GP) Ia gene, designated C807 and T807, are associated with low or high platelet GPIa-IIa density and consequently with slower or faster rate of platelet adhesion to type I collagen, respectively. This polymorphism could therefore present a genetic predisposition for the development of thrombotic disease and hemostasis. We investigated the relationship of the GPIa C807T dimorphism to the risk of coronary artery disease (CAD) and myocardial infarction (MI). An allele-specific polymerase chain reaction (PCR) was developed for genotyping of C807T polymorphism. DNA samples from 2237 male patients who underwent coronary angiography on account of coronary heart disease as verified illness or presumptive diagnosis were genotyped. The odds ratio was calculated as an estimate of the relative risk by multiple logistic regression. We found a strong association between the T allele and nonfatal MI among individuals younger than the me...
Research Interests: Genetics, Polymorphism, Adhesion, DNA, Platelet, and 15 moreHumans, Blood, Male, Genetic determinism, Risk factors, Integrins, Clinical Sciences, Middle Aged, Coronary Angiography, Myocardial Infarction, Age Factors, Risk Factors, Integrin, Cardiovascular medicine and haematology, and Paediatrics and reproductive medicine
Maternal anti-HPA-1a alloantibodies are responsible for most cases of severe fetal and neonatal alloimmune thrombocytopenia (FNAIT). The presence of HPA-1a alloantibodies in maternal blood alone does not predict the fetal platelet (PLT)... more
Maternal anti-HPA-1a alloantibodies are responsible for most cases of severe fetal and neonatal alloimmune thrombocytopenia (FNAIT). The presence of HPA-1a alloantibodies in maternal blood alone does not predict the fetal platelet (PLT) count, and the predictivity of antibody titers determined by enzyme immunoassays (EIAs) is debated. In contrast to EIA, surface plasmon resonance (SPR) provides information on antibody-binding properties. Sequential sera from pregnant women with expected FNAIT were assessed for HPA-1a alloantibodies using SPR. Group I (n = 6) was treated with intravenous immunoglobulin (IVIG) and steroids beginning at 19 weeks of gestation (w.g.), and Group II (n = 4) received intrauterine PLT transfusions (IUT) beginning at 22 w.g. Maternal alloantibodies were quantified using an HPA-1a monoclonal antibody (MoAb) as a standard. Antibody avidity was determined as the ratio of B700 (end of the dissociation phase) to B350 (end of the association phase); the area under the curve (AUC) was calculated to determine overall antibody binding. After 22 w.g., alloantibody characteristics remained stable in both groups, while there was a steep decrease in B700 and B350 values between 16 and 22 w.g. (assessed only in Group I), indicating a decrease in anti-HPA-1a alloantibody concentrations. Interestingly, the AUCs of the last maternal sample before elective delivery appeared to be correlated with fetal and neonatal PLT counts (p = 0.014 and 0.017, respectively). SPR provides quantitative information on HPA-1a alloantibody characteristics in addition to monoclonal antibody-specific immobilization of platelet antigens. SPR results can be calibrated using a MoAb standard and should be further assessed for a potential correlation with fetal PLT count.
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Mild hyperbilirubinemia is a clinical feature of hemolysis. Here we describe a boy with marked elevation of serum bilirubin values (maximum: 70 mg/dL) during an acute episode of autoimmune hemolytic anemia, which returned to within the... more
Mild hyperbilirubinemia is a clinical feature of hemolysis. Here we describe a boy with marked elevation of serum bilirubin values (maximum: 70 mg/dL) during an acute episode of autoimmune hemolytic anemia, which returned to within the reference range after clinical improvement. The boy was a homozygous carrier of short alleles of the heme oxygenase-1 (HO-1) gene GT dinucleotide-repeat promoter polymorphism, which is associated with increased activity and inducibility of the heme-degrading enzyme HO-1, which catalyzes the production of bilirubin. In addition, heterozygosity of the uridine 5'-diphosphate-glucuronosyl-transferase 1A1 promoter polymorphism that is linked with Gilbert syndrome was found in this patient. Because bilirubin production plays a critical role during the neonatal period, the HO-1 promoter polymorphism may be an important genetic factor for the clinical outcome of neonatal hyperbilirubinemia.
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SummaryBernard-Soulier syndrome (BSS) is an extremely rare hereditary bleeding disorder, caused by mutations occurring in the Glycoprotein (GP) Ibα, GPIbβ and GP9 genes that encode for the corresponding subunits of platelet GPIb-V-IX... more
SummaryBernard-Soulier syndrome (BSS) is an extremely rare hereditary bleeding disorder, caused by mutations occurring in the Glycoprotein (GP) Ibα, GPIbβ and GP9 genes that encode for the corresponding subunits of platelet GPIb-V-IX adhesion receptor complex. BSS has been reported in many populations, mostly behaving in an autosomal-recessive manner. While the great majority of BSS mutations are unique to a single individual or family, the GP9 1828A>G Asn45Ser mutation, which we have identified in an undocumented Australian Caucasian, has already been reported in multiple unrelated Caucasian families from various Northern and Central European countries. Haplotype analysis of 19 BSS patients from 15 unrelated Northern European families (including 2 compound heterozygote siblings from a British family previously published, and 17 1828A>G Asn45Ser homozygotes), showed that 14 of these BSS patients from 11 of the 1828A>G Asn45Ser homozygote families share a common haplotype at...
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Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a bleeding disorder caused by transplacental passage of maternal antibodies to fetuses whose platelets (PLTs) express the corresponding human PLT antigen (HPA). We observed a fetus... more
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a bleeding disorder caused by transplacental passage of maternal antibodies to fetuses whose platelets (PLTs) express the corresponding human PLT antigen (HPA). We observed a fetus with FNAIT who died from a severe intracranial hemorrhage. Analysis of maternal serum in antigen capture assay with paternal PLTs showed reactivity with PLT glycoprotein (GP)IIb/IIIa (α(IIb) β(3) ) and GPIa/IIa (α(2) β(1) integrin), indicating the presence of anti-HPA-1a and an additional alloantibody against GPIa (termed anti-Swi(a) ). By immunochemical studies, the localization of the Swi(a) antigen on GPIa/IIa could be confirmed. Analysis of paternal GPIa full-length cDNA showed a single-nucleotide substitution C(3347) T in Exon 28 resulting in a Thr(1087) Met amino acid substitution. Testing of family members by polymerase chain reaction-restriction fragment length polymorphism using MslI endonuclease showed perfect correlation with phenotyping...
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ABSTRACT FMAIT occurs in ∼1 in 1200 births, of which 10–20% have serious bleeding, i.e. intracranial haemorrhage (ICH). Management of such pregnancies needs to balance the risk of bleeding against the known risk of fetal blood sampling... more
ABSTRACT FMAIT occurs in ∼1 in 1200 births, of which 10–20% have serious bleeding, i.e. intracranial haemorrhage (ICH). Management of such pregnancies needs to balance the risk of bleeding against the known risk of fetal blood sampling (FBS).S tudy This was a nonrandomised observational study of FMAIT due to anti-HPA-1a. All cases were managed by an initial FBS, then a) intravenous immunoglobulin (IVIgG), b) regular intrauterine platelet transfusions (IUT), c) neither of above, but FBS ± 1 IUT predelivery, d) no treatment. All babies with a previous sibling known to have platelets < 20 × 109/L or an ICH were considered high risk.R esults 43 pregnancies (44 babies) were analysable giving 49 results in total (more than 1 management in 5).In (a) there was one case with ICH. The resultant platelet count was ≥ 50 × 109/L in 10 cases, and 6 of these were high risk (5 ICH, 1plts < 20 × 109/L). No significant side-effects of treatment occurred. In (b) the number of high risk cases was greater than (a) and there were 2 cases of ICH. The pre-IUT platelet count was < 20 × 109/L on at least 50% of occasions in 10 cases. Overall 12 babies needed to be delivered because of complications caused by FBS/IUT, 4 at less than 32 weeks gestation. There were few cases in (c) and no cases in (d).C onclusions The incidence of ICH in the study group is less than the incidence of ICH in untreated siblings. However, complications from FBS/IUT were significant, and the platelet count was not consistently maintained at > 20 × 109/L. Further studies are required to define the optimal antenatal management of FMAIT.
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Human platelet and neutrophil antigens (HPAs, HNAs) are targets for platelet or granulocyte antibodies causing immune thrombocytopenia or neutropenia, respectively. Currently, genotyping is replacing phenotyping as the preferred method of... more
Human platelet and neutrophil antigens (HPAs, HNAs) are targets for platelet or granulocyte antibodies causing immune thrombocytopenia or neutropenia, respectively. Currently, genotyping is replacing phenotyping as the preferred method of diagnosis of immune cytopenia. To establish a reliable genotyping analysis, however, the availability as reference DNA of genomic DNA from persons of known genotype is essential. By the use of Epstein-Barr virus transformation, panels of B-lympho-blastoid cell lines (B-LCLs) from HPA- and HNA-phenotyped individuals were developed. Genomic DNA was isolated from these cell lines and tested as reference DNA for genotyping of persons for HPAs and HNAs. DNA derived from these B-LCLs was typed by polymerase chain reaction-restriction fragment length polymorphism and -sequence-specific primers. The results were in accordance with the genotyping from peripheral blood cells. These results were confirmed by 24 laboratories in Germany in a blind study. The inexhaustible source of reference DNA derived from B-LCLs allowed the evaluation of reliable HPA and HNA genotyping for quality control purposes. It should facilitate the development of DNA typing in blood centers and clinical laboratories.
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Patients receiving cellular blood components may form HLA antibodies and platelet-specific alloantibodies. Serum samples from a cohort of 252 patients with hematologic or oncologic diseases who are receiving cellular blood components were... more
Patients receiving cellular blood components may form HLA antibodies and platelet-specific alloantibodies. Serum samples from a cohort of 252 patients with hematologic or oncologic diseases who are receiving cellular blood components were studied for platelet-reactive antibodies. Specificity of platelet alloantibodies was determined with a panel of typed platelets Platelet-reactive antibodies were detected in the sera of 113 patients (44.8% of 252), HLA antibodies in the sera of 108 (42.9%), and platelet-specific antibodies in the sera of 20 (8%). The following platelet-specific antibodies were identified: anti-HPA-5b (n = 10), anti-HPA-1b (n = 4), anti-HPA-5a (n = 2), anti-HPA-1a (n = 1), anti-HPA-2b (n = 1), anti-HPA-1b+5b (n = 1), and anti-HPA-1b+2b (n = 1). Fifteen sera from the 108 patients with anti-HLA (13.9%) contained additional platelet-specific alloantibodies, while in 5 sera, platelet-specific alloantibodies only were detected: anti-HPA-5b (n = 4) and anti-HPA-1a (n = 1). Of the 108 sera with HLA antibodies, 29 (26.9%) showed discordant results when studied with the lymphocytotoxicity test and the glycoprotein-specific immunoassay. Ten sera contained panreactive antibodies against platelet glycoproteins (GP) IIb/IIIa, GPIa/IIa, and/or GPIb/IX. Alloimmunization occurred in 58.3 percent of female patients with previous pregnancies, but in only 23.3 percent of those without previous pregnancies (p = 0.0049). Platelet alloantibody specificities in transfused patients (predominantly anti-HPA-5b and -1b with antigen frequencies <30% among whites) differ significantly from those observed in patients with neonatal alloimmune thrombocytopenia or posttransfusion purpura, in whom anti-HPA-1a (antigen frequency >95%) is the most prevalent specificity. HLA antibody detection yields discordant results when the lymphocytotoxicity assay and a glycoprotein-specific immunoglobulin-binding assay are used.
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SummaryThe integrin αIIbβ3 is the major fibrinogen receptor on the platelet membrane and plays a crucial role for platelet aggregation. The β3-subunit carries the human platelet alloantigen (HPA)-1a, which is the main target for... more
SummaryThe integrin αIIbβ3 is the major fibrinogen receptor on the platelet membrane and plays a crucial role for platelet aggregation. The β3-subunit carries the human platelet alloantigen (HPA)-1a, which is the main target for alloantibodies (alloabs) responsible for foetal and neonatal alloimmune thrombocytopenia (FNAIT) and post-transfusion purpura (PTP).Whereas PTP is almost invariably associated with severe bleeding, the clinical presentation of FNAIT ranges from mild thrombocytopenia to severe haemorrhagic diathesis. However, this clinical heterogeneity is not fully understood as it is not explained solely by the variability of the platelet count. Here, we examined the ability of HPA-1a alloabs from mothers with FNAIT (n = 43) and PTP patients (n = 8) to inhibit cell adhesion to fibrinogen and asked if this inhibition was correlated with the heterogeneity of the clinical picture. Stably transfected cells expressing HPA-1a (β3-Leu33) and –1b (β3-Pro33) isoforms were incubated ...
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SummaryImmune mediated heparin induced thrombocytopenia (HIT) is a prothrombotic adverse effect of heparin. However, only a subgroup of patients with HIT develops thromboembolic complications. We aimed to identify risk factors for... more
SummaryImmune mediated heparin induced thrombocytopenia (HIT) is a prothrombotic adverse effect of heparin. However, only a subgroup of patients with HIT develops thromboembolic complications. We aimed to identify risk factors for developing HITassociated thrombosis. We analyzed a registry of patients with clinical suspicion of HIT who tested positive using a sensitive functional assay. Patient information was obtained by a standardized questionnaire. By multivariate analysis the association of age, gender, type of patient population, and magnitude of the platelet count decline with the frequency, type (venous or arterial), and temporal pattern of thrombotic events was assessed. In 408 HIT patients we observed predominance of venous thrombosis (2.4:1), with 40% of patients developing a pulmonary embolism. However, in the subgroup of post-cardiovascular surgery patients there was predominance of arterial thrombosis (1:8.5). The type of arterial thrombosis (limb artery thrombosis >...
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We have evaluated the effect of maternal intravenous immunoglobulin G (ivIgG) treatment on platelet counts in fetal alloimmune thrombocytopenia. Seven patients were studied. All of them were multiparous women who had been immunized... more
We have evaluated the effect of maternal intravenous immunoglobulin G (ivIgG) treatment on platelet counts in fetal alloimmune thrombocytopenia. Seven patients were studied. All of them were multiparous women who had been immunized against the HPA-1a antigen during previous pregnancies and had given birth to at least one severely thrombocytopenic infant. In this study, umbilical blood collection was performed first at the 20th week of gestation and repeated 2-13 times (mean 6 times), depending on the degree of fetal thrombocytopenia. Fetal platelet counting was combined with intrauterine transfusion of 20-30 ml of HPA-1a-negative platelet concentrates to prevent bleeding following umbilical cord puncture. Initial fetal platelet counts ranged from 10,000 to 91,000 per microliters. Maternal treatment with ivIgG (1 g per kg body weight; mean dose 70 g) was given once a week over 7 weeks. In five of seven cases, the basal platelet count did not rise and in two of these cases, it decreased during maternal ivIgG treatment. In one fetus, the baseline platelet count increased from 10,000 to 35,000 per microliters during ivIgG, and in another fetus from 23,000 to 64,000 per microliters. Our observations suggest that ivIgG has no definite benefit for fetal alloimmune thrombocytopenia. Since platelet counts can be very low, careful fetal monitoring by umbilical blood sampling is required. Frequent platelet transfusions in short intervals may be necessary to increase platelet counts in extremely thrombocytopenic fetuses.
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Investigation of the maternal serum in a case of suspected alloimmune neonatal thrombocytopenia by conventional, second-generation platelet serological assays (platelet radioactive antiglobulin test [PRAT], platelet suspension... more
Investigation of the maternal serum in a case of suspected alloimmune neonatal thrombocytopenia by conventional, second-generation platelet serological assays (platelet radioactive antiglobulin test [PRAT], platelet suspension immunofluorescence test [PSIFT] and solid-phase adherence assay (SPAA, 'Capture-P') demonstrated only the presence of HLA class-I antibodies of limited specificities: no platelet-specific antibodies were detectable. The use of a third generation, glycoprotein capture assay (monoclonal antibody-specific immobilization of platelet antigens, MAIPA) revealed the additional presence of anti-HPA-5b with a titre of 1 in 32. Despite this relatively high titre, and the fact that it was able to induce a prolonged thrombocytopenia, this antibody was not detectable by conventional assays. In view of these findings we conclude that the use of MAIPA is essential when investigating cases of suspected alloimmune neonatal thrombocytopenia.
Research Interests: Risk, Pregnancy, Case Report, Humans, Autoimmune diseases, and 15 moreFemale, Male, Prenatal, Transfusion medicine, Thrombocytopenia, Phenotype, Clinical Sciences, Newborn Infant, Adult, Prenatal Diagnosis, Immunophenotyping, Epitopes, Blood component transfusion, Blood platelets, and Paediatrics and reproductive medicine
Research Interests: Polysaccharides, Medicine, Biopsy, Germany, Prospective studies, and 15 moreAllergy, Humans, Female, Pulmonary Embolism, Male, Follow-up studies, Skin, Incidence, Anticoagulants, Middle Aged, Prognosis, Mayo Clinic Proceedings, Severity of Illness Index, Drug hypersensitivity, and Medical and Health Sciences
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Among the most frequent adverse effects of subcutaneous heparin treatment, heparin-induced skin lesions occur with an incidence of 10.3% in nonpregnant female patients. Clinical observations suggest an even higher risk during pregnancy.... more
Among the most frequent adverse effects of subcutaneous heparin treatment, heparin-induced skin lesions occur with an incidence of 10.3% in nonpregnant female patients. Clinical observations suggest an even higher risk during pregnancy. We sought to determine the incidence and causes of heparin-induced skin reactions during pregnancy in a prospective cohort study. Pregnant women with subcutaneous heparin treatment were prospectively examined for skin reactions. If a skin lesion was observed, further diagnostics were performed (skin biopsy, subcutaneous provocation, clinical/laboratory assessment for thrombosis, bleeding, and heparin-induced thrombocytopenia [HIT]). Safety parameters were also analyzed (cross-allergies, frequency of thromboembolic and bleeding complications, HIT, and pregnancy outcome). Among 111 pregnant patients, 22 (19.8%) had heparin-induced skin reactions (95% CI, 13% to 29%). All lesions were caused by allergic delayed-type hypersensitivity (DTH) reactions and not by HIT or other rare conditions. The median time of onset was 50.5 days (range, 5-184 days). The cross-reactivity rate was 33.3%. While nadroparin treatment exhibited a higher DTH risk than dalteparin (hazard ratio [HR], 26.7; 95% CI, 3.4-211.0; P = .00187), enoxaparin treatment was not significantly different from dalteparin treatment (HR, 5.6; 95% CI, 0.3-96.1; P = .238). Three thromboembolic events and 1 major bleeding event occurred. Among patients receiving long-term heparin anticoagulation during pregnancy, heparin-induced skin lesions are frequent (incidence, 19.8%) and are all caused by allergic DTH reactions. Nadroparin has the highest frequency of skin lesions (approximately 65% at 100 days), which is significantly higher than that of dalteparin (HR, 26.7). Therefore nadroparin use should be avoided in pregnancy when possible.
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Abnormalities in alveolar coagulation occur in idiopathic pulmonary fibrosis (IPF). Anticoagulants attenuate bleomycin-induced lung fibrosis in animals. In this study, we first examined the pharmacokinetics of inhaled heparin in healthy... more
Abnormalities in alveolar coagulation occur in idiopathic pulmonary fibrosis (IPF). Anticoagulants attenuate bleomycin-induced lung fibrosis in animals. In this study, we first examined the pharmacokinetics of inhaled heparin in healthy subjects. Second, we investigated the safety and tolerability of heparin inhalation in IPF patients. Coagulation assays were performed in blood and bronchoalveolar lavage fluid samples from 19 healthy volunteers after inhalation of increasing amounts of unfractionated heparin. The acute effects of heparin inhalation on lung function and exercise capacity and the safety and tolerability of chronic heparin inhalation for 28 days were assessed in 20 IPF patients in an open-label exploratory pilot study. In healthy subjects, inhalation of 150,000 IU heparin ("filled dose") significantly increased the partial thromboplastin time and anti-factor Xa activity in blood samples indicating the threshold dose. The local alveolar anticoagulant effect was detectable up to 72 h, and the alveolar half-life was estimated at 28 h. In IPF-patients, no acute deleterious effects on pulmonary function, gas exchange, or exercise capacity were noted after inhalation of the threshold dose. During chronic treatment, where one-fourth of the threshold dose was inhaled every 12 h for 28 days to obtain a steady-state anticoagulant activity in the alveolar space approximating the anticoagulant activity observed after threshold dose inhalation, no heparin-related side effects, such as hemoptysis or heparin-induced antibodies and thrombocytopenia, were detected in any patient, and median lung function values, exercise capacity, and quality of life scores appeared largely unaltered. Three adverse and one serious adverse events were noted; however, the relation of these events to the heparin inhalation was assessed as "unlikely" or "no relation" in each case. Inhaled heparin appears to be safe and well tolerated in IPF patients. Future clinical trials are required to demonstrate the long-term safety and efficacy of inhaled heparin in IPF.