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ABSTRACT: Oculocutaneous albinism (OCA) in combination with a platelet function defect caused by a disturbed release reaction from platelet δ-granules (storage pool defect - SPD) is typical for the autosomal recessive inherited Hermansky-Pudlak syndrome (HPS).
A girl (age: 13 years) with OCA was hospitalized with transfusion-requiring menorrhagia. The suspicion of HPS was confirmed by results of lumi-aggregometry. Suspecting a disorder in primary haemostasis treatment with tranexamic acid (10 mg/kg body weight every 8 h i. v.), desmopressin (0.3 µg/kg body weight every 8 to 12 h) and hormonal therapy (norethisterone) was started but the menorrhagia persisted. Clinical response was finally achieved by a single injection of 100 µg/kg body weight recombinant factor VIIa (rFVIIa).
The diagnosis of HPS should be suspected in patients with OCA and bleeding symptoms and is confirmed by the proof of SPD. In case of absent clinical response to desmopressin the application of rFVIIa should be considered. Hormones and antifibrinolytics are useful options in the treatment of extensive menorrhagia.
Hamostaseologie 11/2011; 31 Suppl 1:S61-3. · 1.19 Impact Factor
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ABSTRACT: Coagulation parameters were determined in children with valproic acid mono- and valproic acid-lamotrigin combination therapy. Patients, methods: Monotherapy group (n = 22; mean age: 10.5 years) was compared to combination therapy (n = 7; 12.9 years) and a control group (n = 22; 8.7 years). The following parameters were measured: aggregation and ATP-release in whole blood (ADP: 20 μmol/l, collagen: 1 μg/ml, thrombin: 0.5 U/ml), PFA-100® closure times (CT), blood cell counts, global tests, VWF:Ag, VWF:CBA, factors VIII and XIII as well as fibrinogen. Bleeding symptoms were evaluated by using a questionnaire. Results: For ADP- and collagen-induced aggregation as well as for ATP release no significant differences between the groups were detected. The combined therapy group showed significantly prolonged CT. Von Willebrand disease was not detected in any of the patients. The platelet count was significantly decreased in the monotherapy group. In six children a mild bleeding tendency was observed, mostly epistaxis. Conclusion: A clinically relevant influence of valproic acid on haemostasis was found only in few cases. However, before surgical procedures an extended coagulation diagnostics is recommended in patients with valproic acid therapy.
Hamostaseologie 11/2010; 30 Suppl 1:S132-7. · 1.19 Impact Factor
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ABSTRACT: In this paper a new tool to assess viscoelastic and dielectric properties of human fluids is presented. Shear horizontal polarized surface acoustic waves (SH-SAW) are used to detect the viscoelastic properties of coagulating blood and blood plasma samples. One-port SAW resonators, with fundamental modes of 85, 170 und 340 MHz were developed. Additionally, their electrode structures can be used simultaneously to detect the dielectric behavior of the whole system by impedance spectroscopy while the frequency ranges from kHz to MHz. The combination of both methods offers the detection of clinical relevant blood parameters like the blood coagulation time and the hematocrit value within one measurement.
Engineering in Medicine and Biology Society (EMBC), 2010 Annual International Conference of the IEEE; 10/2010
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ABSTRACT: In this paper a new tool to assess viscoelastic and dielectric properties of human fluids is presented. Shear horizontal polarized surface acoustic waves (SH-SAW) are used to detect the viscoelastic properties of coagulating blood and blood plasma samples. One-port SAW resonators, with fundamental modes of 85, 170 und 340 MHz were developed. Additionally, their electrode structures can be used simultaneously to detect the dielectric behavior of the whole system by impedance spectroscopy while the frequency ranges from kHz to MHz. The combination of both methods offers the detection of clinical relevant blood parameters like the blood coagulation time and the hematocrit value within one measurement.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 01/2010; 2010:3499-502.
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12/2006: pages 229-234;
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Ultrasonics Symposium, 2005 IEEE; 10/2005
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ABSTRACT: The risk of venous thromboembolism associated with long-haul flights is the subject of controversy. In a prospective, controlled study, we examined 160 passengers before and after return from a long-haul flight and 160 age-matched and sex-matched, non-travelling volunteers using venous compression ultrasound. Deep vein thrombosis was not observed in either group. Isolated calf muscle vein thrombosis (ICMVT) was present in 4/160 (2.5%) flight passengers and in 1/160 (0.6%) controls. All subjects with ICMVT were clinically asymptomatic, and ICMVT was located in the soleal muscle veins in all four subjects. Three of the four passengers with ICMVT had other risk factors for thrombosis.
Blood Coagulation and Fibrinolysis 01/2003; 13(8):755-7. · 1.24 Impact Factor
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ABSTRACT: Activated protein C (APC) resistance and factor V Leiden mutation are major risk factors for deep venous thrombosis. Previous work has led to the view that the coagulation phenotype and the genetic defect are associated in almost all patients. It has been reported about single APC-resistant patients without associated factor V Leiden, but significance and thrombotic risk of this constellation have not yet been established.
We tested 486 consecutive patients with deep venous thrombosis, arterial disease or other than vascular disease for APC-resistance with a factor VIII based assay.
149 patients (31%) showed a pathological APC-ratio. Sensitivity and specificity for detection of factor V Leiden were 100% and 40%, respectively. At 6 months follow-up APC-ratio returned to normal in 55% of the patients with initial pathological APC-resistance. At 12 months follow-up 91% of the patients with persistent APC-resistance showed a pathological ratio as well.
Patients with APC-resistance not due to factor V Leiden can be attributed to one subset with reversible APC-resistance--possibly due to a hypercoagulable state in an acute thrombotic situation, and to another with persistent APC-resistance.
VASA.: Zeitschrift für Gefässkrankheiten. Journal for vascular diseases 03/2001; 30(1):24-7. · 1.31 Impact Factor
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ABSTRACT: LDL apheresis is highly efficient in reducing elevated plasma cholesterol. Due to strict indications only patients with severe, refractory hypercholesterolemia are treated with this method. Mutations in the LDL receptor gene are major genetic causes for severe hypercholesterolemia. Screening the entire gene in LDL apheresis patients from Saxony should determine whether an increased frequency of defined mutations is responsible for the atherogenic hypercholesterolemia in this group. 31 unrelated patients (15 male, 16 female, age 33-71 yrs.) were included in the analysis. The LDL-R gene was screened using SSCP and/or automated sequencing. The familial defective apolipoprotein B-100 (FDB) mutation was genotyped using established PCR techniques. Nineteen of 31 patients were carriers of an LDL-R mutation. Ten missense and two nonsense mutations, three insertions and two deletions were detected. The mutations C74S, C74R, T87M, 660delC, 662insCCCCG, 680insGGACAAATCTGA, 1428insC and 2167delG have not been previously described. One patient was compound heterozygous for two missense mutations. Two further patients were heterozygous for FDB. No mutations were found among controls. A genetic background for hypercholesterolemia in the LDL-R could be established in about 61% of the patients examined. Therefore, methods of DNA analysis allow to recognize and adequately treat a large portion of high-risk individuals at an early stage.
Human Mutation 02/2001; 17(1):76-7. · 5.69 Impact Factor
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ABSTRACT: In this study we investigated a group of patients in whom a resistance to APC (activated protein C) was found but no Leiden mutation existed in the presence of missense mutations in the first 1200 bp of the Exon 13 (B-domain) in the factor V (FV) gene. The determination of the APC response was performed using the Immunochrom(R) APC response Test Kit. The mutations were determined by temperature gradient gel electrophoresis and DNA sequencing. In the APC-resistant patients without the FV Leiden, we found 4 silent mutations (2298C>T, 2325T>C, 2379A>G, 2391A>G) and 4 missense mutations (2540A>C, 2663A>G, 2684A>G, 2863A>G), which code for the amino acids N789T (GenBank Accession # AF119360), K830R, H837R, and K897E. In all of the patients and controls, the polymorphisms at nucleotide positions 2391, 2663, 2684, and 2863 appeared to be associated. In the major allele all bases are A (A allele) and in the minor allele are G (G allele). A significantly lower G allele frequency was observable in the patient group than in the control group (0.14 vs. 0.31; p<0.05). The frequency of the 2540C allele, which is associated with the 2379G and the 4070G allele (non-Leiden!), did not differ significantly between the patient and the control groups. We suggest that the G allele, which is not associated with the FV Leiden mutation, as well as the [2379G; 2540C; 4070G] allele have no influence on the APC cofactor function itself, or only subtly as determined in the test systems used.
Thrombosis Research 10/2000; 99(6):539-47. · 2.44 Impact Factor
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ABSTRACT: The factor V (FV) B-domain is extremely important to the cofactor function of native FV for activated protein C (APC) in the inactivation of factor VIII (FVIII). In a previous study, we found that in the B-domain coding portion of DNA, the polymorphisms at nucleotide positions 2391, 2663, 2684, and 2863 were associated. In the major allele, all bases are A (A allele) and those in the minor allele are G (G allele). This study concerns itself with the question of whether or not there are differences in the APC response between the A allele and the G allele in plasma samples from persons without the FV Leiden. The APC ratios of homozygous carriers of the major A allele and the minor G allele do not differentiate themselves in classical activated partial thromboplastin time-based assays. In contrast, a test based on the deactivation of FVIII in the tenase complex in homozygous carriers of the minor G allele showed significantly lower APC ratios (P = 0.001) in comparison with the major A allele. The results of the investigation after modification of the test indicate that mutative changes in the B-domain apparently influence the interaction among phospholipids, APC, FV, and protein S. An increase in FVIII through the introduction of the FVIII concentrate Kogenate to the plasma samples was associated with a drop in the APC ratios of both genotypes. After defining 59 age- and sex-based matched pairs without the FV Leiden, the observed frequency of the minor G allele was higher in the non-thrombotic group (33.0%) than in the thrombotic group (22.8%). However, the difference did not reach the level of significance (odds ratio, 0.53; 95% confidence interval, 0.26-1.12). It does, nevertheless, appear possible that a homozygous condition for the minor allele in combination with a defect known to be associated with thrombophilia represents an additional thrombogenetic risk factor.
Blood Coagulation and Fibrinolysis 10/2000; 11(6):519-27. · 1.24 Impact Factor
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ABSTRACT: To evaluate the role of inherited thrombophilia in the development of central venous line (CVL)-related thrombosis, the following parameters were determined in 77 pediatric-oncologic patients with CVL: activated protein C (APC)-ratio, factor V (FV) G1691A and prothrombin G20210A mutation, protein C, protein S, antithrombin, coagulation factor XII, lipoprotein (a) and homocysteine. An inherited prothrombotic risk factor was found in 17 patients (23%). Four out of 14 patients with a single detect (hyperlipoproteinemia, heterozygous FV G1691A and prothrombin G20210A mutation, protein C deficiency type I) and all three patients with combined defects (heterozygous FV G1691A mutation combined with heterozygous prothrombin G20210A variant, protein S deficiency or hyperlipoproteinemia) suffered from CVL-related thrombosis. In 11 out of 77 patients (14%) a CVL-related thrombosis was detected. In 2 children thrombosis occurred a few days after asparaginase therapy and in another three thrombosis was associated with CVL-related septicemia caused by Staphylococcus epidermidis. After removal of CVL, thrombosis was detected in 5 children, in 2 without clinical symptoms but in the presence of inherited prothrombotic risk factors. CONCLUSION: The present study demonstrates the clinical importance of CVL in combination with inherited thrombophilia in the development of thrombosis in pediatric-oncologic patients. Before or shortly after insertion of CVL, patients should be tested for the presence of factor V G1691A mutation, prothrombin G20210A variant and increased lipoprotein (a) values.
European Journal of Pediatrics 01/2000; 158 Suppl 3:S147-50. · 1.88 Impact Factor
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ABSTRACT: Hepatic lipase is an enzyme which hydrolyzes triglycerides from plasma lipoproteins and thus takes part in the metabolism of intermediate density lipoproteins and high-density lipoproteins. The search described here concentrated on mutations of the HL gene in 129 patients with combined hypertriglyceridemia/hyperalphalipoproteinemia and in 184 members of 19 families with familial combined hyperlipidemia. Controls were 100 subjects with favorable lipid values (age 46-51 years). Mutation screening and analysis were performed by temperature-gradient gel electrophoresis, allele-specific restriction genotyping, and sequencing. Six different missense mutations and four different silent mutations were found in the HL gene. The alleles Phe-267 and Gln-343 were detected only once in the patient group with hypertriglyceridemia and hyperalphalipoproteinemia and were not detected in the control group. The allele Met-383 was rare in both patients and controls. We found 9.3% of the patients and only 3.0% of controls to be carrying the Val-73-Met missense mutation. The allele Phe-334 was found in 5.43% of patients and in 2.0% of controls. The difference between the frequencies of these alleles was significant between male patients and male controls (Met-73 P=0.044; Phe-334 P=0.047). Also, the summarized odds ratio of 3.28 (95% confidence interval 1.23-8.73) demonstrates that mutation carriers are significantly more prevalent in the patients. Fifteen carriers of the Met-73 allele were found in six families of the familial combined hyperlipidemia group. Furthermore, six carriers of the Phe-334 allele were found in three families of the same group. In comparison to the controls the summarized odds ratio of 2.45 (95% confidence interval 0.89-6.71) barely missed the level of significance. The linkage between genotype and phenotype was incomplete. These results show an association of the missense mutations Val-73-Met and Leu-334-Phe as susceptibility alleles for combined forms of hyperlipidemia.
Journal of Molecular Medicine 11/1999; 77(10):728-34. · 4.67 Impact Factor
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Human Mutation 11/1999; 14(4):357. · 5.69 Impact Factor
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S Gehrisch
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ABSTRACT: The accumulation of triglyceride-rich lipoproteins is an independent factor for an increased risk for premature arteriosclerosis. Common mutations in the lipoprotein lipase (LPL) gene are at least in part inherited susceptibility factors involved in the age- and sex-dependent phenotypic expression of hypertriglyceridemia. It can be estimated that about 20% of patients with hypertriglyceridemia are carriers of common LPL gene mutations (Asp9Asn, Asn291Ser, Trp86Arg, Gly188Glu, Pro207Leu, Asp250Asn) associated with the HLP. Genotyping of these LPL gene mutations is recommended especially in patients with high risk for premature arteriosclerosis. A comparably high number of individuals are carriers of common mutations (Ser447X) or silent mutations (Thr361) associated with low favorable lipids.
Current Atherosclerosis Reports 08/1999; 1(1):70-8. · 2.66 Impact Factor
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ABSTRACT: The growth factor bound protein GRB2, a 25-kDa cytosolic protein, plays a key role in two separate pathways of the insulin signal transduction system leading from the insulin receptor to the Ras proteins and thus affecting mitogenic signaling. GRB2 regulates Ras activation through association with the guanine nucleotide exchange factor Sos. The GRB2/Sos complex can connect with insulin receptor substrate 1 (IRS-1), which is one of the primary targets of the insulin and insulin-like growth factor receptors. In a second pathway, independent of IRS-1, GRB2 links the insulin receptor to Ras signaling through another adapter protein, called Shc. In protooncogenic and other noninsulin signaling systems, GRB2 appears to link receptor tyrosine kinases to Ras in similar pathways as well. This study presents the exon-intron organization of the human GRB2 gene. After primers were placed across the known mRNA sequence, Long PCR products spanning introns and their adjacent splice sites were amplified and adequately sequenced to establish the splice sites and flanking regions. The gene was found to consist of five exons (ranging from 78 to 186 bp) and of four introns (from approximately 1 to approximately 7 kb). Intron primers for the respective exons were generated using the newly found flanking sequences. All exons were successfully amplified and sequenced, and the data obtained from Long PCR sequencing were confirmed.
Genomics 04/1999; 56(2):203-7. · 3.02 Impact Factor
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ABSTRACT: Human hepatic lipase (hHL) plays an important role in hydrolysis of triglycerides from plasma lipoproteins. The enzyme also hydrolyzes HDL2 lipids resulting in smaller HDL particles with a lower cholesterol content and properties similar to HDL3. hHL is localized in liver sinusoids, ovary and adrenal gland. These findings propose an influence on processing of cholesterol. Here we report an insertion mutation in exon 3 of hHL. The 18 bp duplication contains an additional internal point mutation (GenBank-Accession #AF037404). The female mutation carrier suffered from severe adiposity with total cholesterol of 291,6mg/dl, HDL-cholesterol of 55,3mg/dl, LDL-cholesterol of 206,8mg/dl and triglycerides of 80,8mg/dl. Following cloning of a PCR-amplified fragment the mutation was confirmed by cycle sequencing. Sequence analysis revealed an inserted repeat of 18 nucleotides. Furthermore the patient carries an additional missense mutation A-->G at nucleotide 9 of the repeat which results in an amino acid exchange from Ile-->Val at codon 4 of the repeat. These data enable us to report the insertion of HisTyrThrValArgVal which might be responsible for the moderate shift in lipid metabolism of the heterozygous patient.
Human Mutation 01/1998; 12(3):216. · 5.69 Impact Factor
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ABSTRACT: To demonstrate the usefulness of Long PCR in analyzing gene structures and large deletions we have developed a method to amplify the entire LDL receptor gene, including the promoter region and intron 1. This opens new ways for studies of the gene and allows the detection of certain LDL receptor-specific deletions. For the amplification of the LDL receptor gene, spanning approximately 45.5 x 10(3) bases and divided into 18 exons and 17 introns, we have designed overlapping PCR products (ranging from 4 to 16 x 10(3) bases in length), which can be amplified simultaneously overnight for fast results. It was possible to positively identify two samples from heterozygote carriers of the "5 kB French-Canadian" deletion using this method. As a side result the length of intron 1 of the LDL receptor gene could be established to be approximately 9.5 x 10(3) bases. The method is sensitive enough to detect deletions in 1:10 mixes of positive control with wildtype DNA.
European journal of clinical chemistry and clinical biochemistry: journal of the Forum of European Clinical Chemistry Societies 01/1997; 34(12):955-9.
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ABSTRACT: In familial defective apolipoprotein B-100 (FDB) the presence of a mutant apolipoprotein (apo) B-100 (FDB3500Q/W) in LDL markedly reduces their affinity for the LDL receptor, leading to elevated LDL cholesterol levels. However, the hypercholesterolemia in most FDB patients is relatively mild when compared with, e.g., familial hypercholesterolemia (FH). In order to study mechanisms that may partly alleviate the clinical consequences of FDB, we investigated the in vivo kinetics of apoB-100-containing lipoproteins in five FDB heterozygotes (total cholesterol: 7.84 +/- 1.37 mmol/I; total apoB: 1.68 +/- 0.37 g/l; mean +/- SD) and six normolipidemic controls (4.61 +/- 0.62 mmol/l; 0.98 +/- 0.12 g/l) using a stable isotope approach. During and after a 10-12 h primed, constant infusion of either [13C6]phenylalanine or [2H3]leucine, tracer enrichment was determined in apoB-100 from ultracentrifugally isolated VLDL1 (Sf 60-400), VLDL2 (Sf 20-60), IDL (Sf 12-20), LDL1 (Sf 7-12), and LDL2 (Sf 0-7). The rates of apoB-100 production, catabolism, and transfer were estimated by model-based compartmental analysis. The overall fractional catabolic rate (FCR) of IDL apoB-100 in FDB was substantially increased (2.99 +/- 0.68 pools/day vs. 1.70 +/- 0.23 pools/day in controls, P < 0.01). The fractional rate of apoB-100 transfer from IDL to LDL in FDB was decreased (0.97 +/- 0.13 pools/day vs. 1.24 +/- 0.10 pools/day, P < 0.05). The FCR of LDL apoB-100 in FDB was decreased (0.18 +/- 0.07 pools/day vs. 0.56 +/- 0.05 pools/, P < 0.01). Finally, the input rate of LDL apoB-100 in FDB was markedly decreased (9.45 +/- 2.96 mg/kg day1 vs. 15.54 +/- 1.70 mg/kg day1, P < 0.05). Our data suggest that the relatively small increase of LDL concentrations in FDB is due to an increased clearance of LDL precursor particles via the LDL-receptor and apoE-receptors as well as a decreased conversion of IDL to LDL - two mechanisms that distinguish FDB from FH.
The Journal of Lipid Research 10/1996; 37(10):2074-87. · 5.56 Impact Factor
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Zeitschrift für Gastroenterologie 07/1996; 34 Suppl 3:62-3. · 0.90 Impact Factor
