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Biomedical subjects

I Pabinger

Publications and source records attributed to I Pabinger.

At least 55 records · Page 3Linked to original sources
PubMed1998

Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism.

Hyperhomocysteinemia is a risk factor of venous thromboembolism. The risk of recurrence in patients with hyperhomocysteinemia is unknown, and the optimal therapy for these patients after acute venous thromboembolism is uncertain. In a multicenter study, 264 patients with an objectively documented single episode of idiopathic venous thromboembolism were prospectively followed after discontinuation of oral anticoagulants. Patients were classified as hyperhomocysteinemic if their homocysteine levels exceeded the 95th percentile of the controls. The outcome events studied were objectively confirmed deep-vein thrombosis and/or pulmonary embolism. Homocysteine levels were elevated in 66 patients (25%) and normal in 198 patients (75%). Recurrent venous thromboembolism occurred in 12 of 66 patients with hyperhomocysteinemia (18.2%) and in 16 of 198 patients without hyperhomocysteinemia (8.1%). The cumulative probability of recurrence 24 months after discontinuation of oral anticoagulants was 19.2 percent (95 percent confidence interval 8.7-27) in patients with hyperhomocysteinemia and was 6.3 percent (95 percent confidence interval 2.4-10.1; p = 0.001) in those without hyperhomocysteinemia. The relative risk of recurrent thrombosis was higher in patients with hyperhomocysteinemia [RR 2.7 (1.3-5.8), p = 0.009]. Patients with hyperhomocysteinemia are at high risk of recurrent venous thromboembolism. The high prevalence of hyperhomocysteinemia in thrombosis patients together with the increased risk of recurrence warrants extended patient screening. The impact on the risk of recurrence of prolonged anticoagulation, supplementation of folate and vitamin B12, or both have to be investigated.

Adolescent↗
PubMed1997

Evaluation of bedside prothrombin time and activated partial thromboplastin time measurement by coagulation analyzer CoaguCheck Plus in various clinical settings.

In the present study CoaguCheck Plus (CCP), a coagulation test system using whole blood, was evaluated with respect to its comparability with widely distributed conventional routine coagulation assays. A correlation of r = 0.997 (p < 0.0001) was found between INR of CCP-prothrombin time (CCP-PT) and Thrombotest (KC-1 analyzer) in patients on oral anticoagulant therapy. A correlation of r = 0.899 (p < 0.001) between CCP-aPTT and Actin ES aPTT (STA analyzer) was found in heparinized patients. Impaired hepatic hepatic coagulation factor synthesis in liver cirrhosis patients was detected by CCP-PT with a sensitivity of 0.75 and by Normotest (STA analyzer) with a sensitivity of 0.92. Those patients with normal CCP-PT values and liver disease had, only mild reductions (> 30% of normals) in coagulation factors II, V, VII or X. CCP-aPTT was also performed in patients with a deficiency in the so called endogenous coagulation factors VIII, IX, XI and XII. CCP-aPTT showed a sensitivity similar to that of Actin FS aPTT in the detection even of mild deficiencies in factors VIII, IX and XII; factor XI deficiency was however detected only in patients with severe (< 12% of normals) disease; lupus anticoagulants were detected with a high sensitivity.

Blood Coagulation Tests↗
PubMed1997

Granulocyte colony-stimulating factor as an adjunct to induction chemotherapy for adult acute lymphoblastic leukemia--a randomized phase-III study.

Because of the recommendation to avoid the concomitant administration of growth factors and chemotherapy, there is only limited information on colony-stimulating factor (CSF) therapy in acute lymphoblastic leukemia (ALL) induction protocols, in which cytotoxic drugs are administered in divided doses over a prolonged period of time, thus requiring a simultaneous administration of growth factors and chemotherapy. We conducted a prospective, randomized, controlled study to determine the safety and efficacy of granulocyte colony-stimulating factor (G-CSF; filgrastim) as an adjunct to phase I of induction chemotherapy for adult ALL. Patients (n = 53) were randomized to receive no growth factor or G-CSF (5 microg/kg/d subcutaneously) starting on day 2 of chemotherapy consisting of daunorubicin (45 mg/m2) and vincristine (1.5 mg/m2) on days 1, 8, 15, and 22; L-asparaginase (2500 U/m2) on days 1 through 14; and prednisone (60 mg/m2) on days 1 through 28. A total of 25 patients in the G-CSF group and 26 patients in the control arm fulfilled the inclusion criteria of the study. G-CSF markedly ameliorated neutropenia because the median proportion of days with neutropenia less than 1,000/microL was 29% in the G-CSF group as compared with 84% in the control arm (P < .00005). The median time to reach absolute neutrophil counts (ANC) > or = 1,000/microL was 16 days in G-CSF patients and 26 days in controls (P < .001). More importantly, G-CSF significantly reduced the incidence of febrile neutropenia (12% v 42% in controls, P < .05) and documented infections (40% v 77%, P < .05). No significant differences were found with regard to requirements for red blood cell transfusions and platelet concentrates. A total of 24 of 25 (96%) patients in the G-CSF group and 20 of 25 (80%) evaluable control patients had complete remission after phase I of induction therapy. We conclude that G-CSF can be safely administered as an adjunct to induction therapy of ALL and is clinically beneficial by ameliorating neutropenia and reducing infectious complications.

Adolescent↗
PubMed1997

A single genetic origin for a common Caucasian risk factor for venous thrombosis.

A common genetic risk factor for venous thrombosis among Caucasoid subpopulations is a polymorphism, nt G1691A, in blood coagulation factor V that replaces Arg506 with Gln and imparts resistance of factor Va to the anticoagulant, activated protein C. Haplotype analyses using six dimorphic sites in the factor V gene for 117 Caucasian subjects of Jewish, Arab, Austrian, and French origin who were homozygous for nt A1691 compared with 167 controls (nt G1691) support a single origin for this polymorphism. The nt G1691A mutation is estimated to have arisen circa 21,000 to 34,000 years ago, ie, after the evolutionary divergence of Africans from non-Africans and of Caucasoid from Mongoloid subpopulations.

Arginine↗
PubMed1997

Specificities of platelet autoantibodies in patients with lupus anticoagulants in primary antiphospholipid syndrome.

We have studied target platelet antigens in 22 patients with lupus anticoagulants and a primary antiphospholipid syndrome in order to determine whether any specificities of platelet autoantibodies are correlated with thromboembolism, and if these antibodies cross-react with phospholipids, which would suggest their role in the development of thromboembolic disease. Platelet counts were median 203 x 10(9)/l, range 100-298 x 10(9)/l. Platelet antibodies were found in six thrombocytopenic patients and in further nine patients. All these 15 patients had antibodies against GPIIb/ IIIa, five patients against GPIb/IX, and six patients against GPIV. Anti-GPIb/IX and -GPIV occurred only in combination with anti-GPIIb/IIIa antibodies. There was no correlation between the presence of detectable platelet antibodies or any of their glycoprotein specificity and thrombocytopenia or the history of a thromboembolic disease. Eluates from platelets contained only GPIIb/IIIa reactivities, but neither anti-GPIb/IX nor anti-GPIV. None of the eluates contained lupus anticoagulant activity. In one case, the platelet eluates contained anti-GPIIb/IIIa and anticardiolipin IgG antibodies. These results suggest that in patients with a primary antiphospholipid syndrome the presence of platelet autoantibodies neither indicate a risk for thromboembolic disorder nor have lupus anticoagulant activity.

Adolescent↗
PubMed1997

Wilson's disease in patients presenting with liver disease: a diagnostic challenge.

BACKGROUND & AIMS: In patients with Wilson's disease presenting with liver involvement, the correct diagnosis is often missed or delayed. The aim of this study was to find an algorithm for diagnosis of this difficult patient group. METHODS: Clinical and laboratory findings of 55 patients with Wilson's disease were evaluated at diagnosis before treatment. Presenting symptom was chronic liver disease in 17 patients, fulminant hepatic failure in 5 patients, hemolysis in 3 patients, and neurological disease in 20 patients, and 10 patients were detected by family screening (siblings). Evaluation included neurological and ophthalmologic examination, routine laboratory tests, and parameters of copper metabolism including liver copper content in 43 liver biopsy specimens. RESULTS: In the whole group, serum ceruloplasmin level was <20 mg/dL in 73%, urinary copper excretion was increased in 88%, and liver copper content was elevated in 91% at diagnosis. Kayser-Fleischer rings were detected in 55%. In contrast to patients with neurological disease (90% Kayser-Fleischer rings, 85% low ceruloplasmin), only 65% of patients presenting with liver disease were diagnosed by these typical findings. Ceruloplasmin levels were lower in patients with Kayser-Fleischer rings or with neurological disturbances than in patients without these symptoms. CONCLUSIONS: The commonly used clinical and laboratory parameters are not sufficient to exclude the diagnosis of Wilson's disease in patients with liver disease of unknown origin.

Adolescent↗
PubMed1997

Mutation (677 C to T) in the methylenetetrahydrofolate reductase gene aggravates hyperhomocysteinemia in hemodialysis patients.

Hyperhomocysteinemia is frequent in hemodialysis patients and represents an independent risk factor for vascular disease in these patients. Elevated total homocysteine (tHcy) plasma levels can results from defective remethylation of Hcy to methionine due to decreased activity of the enzyme methylenetetrahydrofolate reductase (MTHFR). A genetic aberration in the MTHFR gene (677 C to T substitution) has been shown to result in reduced MTHFR activity. We tested the hypothesis that elevation of tHcy plasma levels in hemodialysis patients is influenced by the 677 C to T mutation of the MTHFR gene and examined the relation of the genotype with tHcy, folate and vitamin B12 plasma levels in these patients. The allelic frequency of the MTHFR mutation was evaluated in 203 patients maintained on chronic hemodialysis treatment. Total Hcy, folate, vitamin B12 levels and the MTHFR mutation were analyzed in 69 of the 203 patients and in 69 age- and sex-matched healthy control subjects. The allelic frequency of the 677 C to T transition in the MTHFR gene in hemodialysis patients was 34.7% versus 35.5% in healthy controls. Of 203 patients 26 (12.8%) were homozygous for the mutation (+/+) versus 10.2% in healthy subjects. The heterozygous (+/-) genotype was identified in 43.8% of patients versus 50.7% in controls. The mean tHcy level in hemodialysis patients was 28.7 +/- 11.0 mumol/liter versus 10.0 +/- 3.0 mumol/liter in control subjects. The mean tHcy levels were 36.4 +/- 13.4 mumol/liter in (+/+) patients and 12.2 +/- 4.5 mumol/liter in (+/+) controls, 28.7 +/- 10.8 mumol/liter in (+/-) patients and 9.9 +/- 2.7 mumol/liter in (+/-) controls and 25.4 +/- 8.5 mumol/liter in (-/-) hemodialysis patients versus 9.7 +/- 2.8 mumol/liter in (-/-) controls: There was no significant difference of folate and vitamin B12 concentrations in patients and controls with different MTHFR genotypes. Analysis of covariance including age, gender, folate concentrations, vitamin B12 levels, albumin and creatinine as covariables revealed a significant influence of the (+/+) genotype, albumin and folate status on tHcy levels in hemodialysis patients. Together, our data demonstrate that the extent of hyperhomocysteinemia in hemodialysis patients is not only the result of uremia or folate status, but is also genetically determined by the (+/+) MTHFR genotype. The presence of the 677 C to T mutation in the MTHFR gene does not appear to represent a risk factor for development of end-stage renal disease.

Adult↗
PubMed1997

Lupus anticoagulants: strong association with the major histocompatibility complex class II and platelet antibodies.

A relationship between the presence of platelet autoantibodies and major histocompatibilty complex class II alleles was determined in 27 patients with lupus anticoagulants. Twenty-two patients had a primary antiphospholipid syndrome' and five patients had lupus erythematosus (SLE). Platelet antibodies against the platelet glycoproteins (GP) IIb/IIIa were detectable in 20 patients. Anti-GPIb/IX or -GPIV antibodies were detectable only in patients with anti-GPIIb/IIIa antibodies. An increased frequency of HLA-DQB1*06 was demonstrable in the total patient population. The association between the lupus anticoagulants and HLA-DQB1*06 was even stronger if patients also had detectable platelet antibodies. This association was also seen if patients with a history of thromboembolic disease were considered separately. However, within the patient population there was no difference between frequencies of HLA alleles detectable platelet antibodies.

Adolescent↗
PubMed1997

A hitherto unknown splice site defect in the protein S gene (PROS1): the mutation results in allelic exclusion and causes type I and type III protein S deficiency.

A hitherto unknown splice site mutation, in the splice acceptor of intron B (tctag to tctgg), was identified in a symptomatic patient with type III protein S deficiency. The mutation co-segregated with type I/III protein S deficiency in the patient's family. RNA analysis showed allelic exclusion of the mutant transcript in affected individuals. The apparent type III deficiency in the propositus was not associated with the protein S Heerlen variant.

Humans↗
PubMed1997

A frequent mutation in the protein S gene results in cryptic splicing.

Protein S is a vitamin K dependent coagulation inhibitor. One of several defects in the protein S gene (PROS1) associated with hereditary deficiency is a G --> A transition at position 5 of the splice donor in intron J. Although the mutation has been reported to cause allelic exclusion, we demonstrated low amounts of alternatively spliced ectopic PROS1 transcripts in carriers of this mutation. Sequencing of mutant RNA indicated the use of a cryptic splice site upstream of the common splice donor. The use of the cryptic splice site results in the deletion of 32 nucleotides at the 3' end of exon 10. The new reading frame contains several premature termination signals.

Humans↗
PubMed1997

The risk of recurrent venous thromboembolism in patients with and without factor V Leiden.

Thromboprophylaxis with oral anticoagulants up to six months is established in patients after a first venous thromboembolic event (VTE). The risk of recurrent VTE is still considerable thereafter, and it is uncertain whether some patients might benefit from extended anti-coagulation. We performed a prospective, multicenter trial (4 thrombosis centers) and evaluated in 380 patients with a first or recurrent VTE (patients with a deficiency of antithrombin, protein C, protein S or plasminogen; cancer; or an antiphospholipid antibody syndrome were excluded) the risk of recurrence after discontinuation of secondary thromboprophylaxis with oral anticoagulants. It was the aim of the study to evaluate whether patients, with factor V Leiden are at an increased risk of recurrent VTE. 112 (29.5%) patients were carriers of factor V Leiden (26.9% heterozygous, 2.6% homozygous). After a median observation time of 19.3 months the overall recurrence rate of VTE was 9.9%. Recurrent deep vein thrombosis and/or pulmonary embolism occurred in 26 of 268 patients without factor V Leiden (9.7%) and in 10 of 112 patients with factor V Leiden (8.9%). The probability of recurrent VTE two years after discontinuation of oral anticoagulants was 12.4% (95% CI 7.8-17) in patients without factor V Leiden and was 10.6% (95% CI 3.8-17.4) in carriers of the mutation. This difference was statistically not significant. Patients with factor V Leiden are not at a higher risk of recurrent VTE within two years after discontinuation of oral anticoagulants than patients without factor V Leiden. Balancing the risk of recurrent VTE and bleeding from oral anticoagulants, patients with factor V Leiden are not likely to benefit from oral anticoagulant therapy extended beyond six months.

Adult↗
PubMed1997

Prothrombin fragment F1+2 is not predictive for recurrent venous thromboembolism.

It would be important to estimate in advance the risk of recurrent thrombosis. Deficiencies of antithrombin, protein C or protein S, or resistance to activated protein C are associated with a biochemically detectable prethrombotic state. It is thus far unknown whether in patients with a history of thromboembolism but without a defined clotting abnormality a heightened coagulation activation is detectable. We investigated the value of prothrombin fragment F1+2 (F1+2) as a predictor of recurrent venous thromboembolism. Furthermore, we compared the F1+2 levels of thrombosis patients without a defined clotting defect to those of Factor V Leiden patients with a history of venous thrombosis and to those of healthy controls. 180 patients without a defined clotting abnormality and 73 patients with Factor V Leiden were prospectively followed after discontinuation of oral anticoagulants for venous thrombosis and F1+2 was measured at regular intervals. Recurrent venous thromboembolism occurred in 23 (9%) of the 253 patients. Before or at several time points after oral anticoagulants, no significant difference in F1+2 levels was found in patients with and without recurrent thrombosis. F1+2 levels at 3 weeks and prior to recurrence were not significantly different in both patient groups. Over a one-year observation period, F1+2 levels of both patients with and without Factor V Leiden were higher than those of the controls. No difference in F1+2 was seen between patients with and without Factor V Leiden. We conclude that monitoring of F1+2 is not suitable for identification of individuals at risk of recurrent venous thrombosis. Permanent hemostatic system activation is detectable both in patients with a defined abnormality of the clotting system and in patients in whom a particular defect has not (yet) been identified.

Adult↗
PubMed1997

Levels of prothrombin fragment F1+2 in patients with hyperhomocysteinemia and a history of venous thromboembolism.

Increased thrombin generation occurs in many individuals with inherited defects in the antithrombin or protein C anticoagulant pathways and is also seen in patients with thrombosis without a defined clotting abnormality. Hyperhomocysteinemia (H-HC) is an important risk factor of venous thromboembolism (VTE). We prospectively followed 48 patients with H-HC (median age 62 years, range 26-83; 18 males) and 183 patients (median age 50 years, range 18-85; 83 males) without H-HC for a period of up to one year. Prothrombin fragment F1+2 (F1+2) was determined in the patient's plasma as a measure of thrombin generation during and at several time points after discontinuation of secondary thromboprophylaxis with oral anticoagulants. While on anticoagulants, patients with H-HC had significantly higher F1+2 levels than patients without H-HC (mean 0.52 +/- 0.49 nmol/l, median 0.4, range 0.2-2.8, versus 0.36 +/- 0.2 nmol/l, median 0.3, range 0.1-2.1; p = 0.02). Three weeks and 3, 6, 9 and 12 months after discontinuation of oral anticoagulants, up to 20% of the patients with H-HC and 5 to 6% without H-HC had higher F1+2 levels than a corresponding age- and sex-matched control group. 16% of the patients with H-HC and 4% of the patients without H-HC had either F1+2 levels above the upper limit of normal controls at least at 2 occasions or (an) elevated F1+2 level(s) followed by recurrent VTE. No statistical significant difference in the F1+2 levels was seen between patients with and without H-HC. We conclude that a permanent hemostatic system activation is detectable in a proportion of patients with H-HC after discontinuation of oral anticoagulant therapy following VTE. Furthermore, secondary thromboprophylaxis with conventional doses of oral anticoagulants may not be sufficient to suppress hemostatic system activation in patients with H-HC.

Administration, Oral↗
PubMed1996

Increased fetal loss in women with heritable thrombophilia.

BACKGROUND: A successful outcome of pregnancy requires an efficient uteroplacental vascular system. Since this system may be compromised by disorders of haemostasis associated with a prothrombotic state, we postulated that maternal thrombophilia might be a risk factor for fetal loss. We studied the relation between heritable thrombophilic defects and fetal loss in a cohort of women with factor V Leiden or deficiency of antithrombin, protein C, or protein S. METHODS: We studied 1384 women enrolled in the European Prospective Cohort on Thrombophilia (EPCOT). Of 843 women with thrombophilia 571 had 1524 pregnancies; of 541 control women 395 had 1019 pregnancies. The controls were partners of male members of the EPCOT cohort or acquaintances of cases. We analysed the frequencies of miscarriage (fetal loss at or before 28 weeks of gestation) and stillbirth (fetal loss after 28 weeks of gestation) jointly and separately. FINDINGS: The risk of fetal loss was increased in women with thrombophilia (168/571 vs 93/395; odds ratio 1.35 [95% Cl 1.01-1.82]). The odds ratio was higher for stillbirth than for miscarriage (3.6 [1.4-9.4] vs 1.27 [0.94-1.71]). The highest odds ratio for stillbirth was in women with combined defects (14.3 [2.4-86.0]) compared with 5.2 (1.5-18.1) in antithrombin deficiency, 2.3 (0.6-8.3) in protein-C deficiency, 3.3 (1.0-11.3) in protein-S deficiency, and 2.0 (0.5-7.7) with factor V Leiden. The corresponding odds ratios for miscarriage in these subgroups were 0.8 (0.2-3.6), 1.7 (1.0-2.8), 1.4 (0.9-2.2), 1.2 (0.7-1.9), and 0.9 (0.5-1.5). Significantly more pregnancy terminations had been done in women with thrombophilia than in controls (odds ratio 2.9 [1.8-4.8]); this discrepancy was apparent in nine of 11 participating centres and for all thrombophilia subgroups. INTERPRETATION: Women with familial thrombophilia, especially those with combined defects or antithrombin deficiency, have an increased risk of fetal loss, particularly stillbirth. Our findings have important implications for therapy and provide a rationale for clinical trials of thromboprophylaxis for affected women with recurrent fetal loss.

Abortion, Spontaneous↗
PubMed1996

Duration of second complete remission in patients with acute myeloid leukemia treated with chemotherapy: a retrospective single-center study.

A total of 168 patients with de novo AML were retreated with chemotherapy at relapse following first CR; 66 patients (39%) achieved a second complete remission (CR). The probability of achieving a second CR was highly dependent on the duration of the first remission. Patients who received no or conventional postremission chemotherapy after second CR had a median remission duration of 7.5 months, and the probability of remaining in remission at 3 years was 24%. Patients with a first CR of more than 12 months had a median second remission duration of 18 months. The probability of a second CCR was 35% at 3 years and 24% at 5 years, whereas none of the patients with a first CR of less than 12 months was in remission at 3 years. Only a poor correlation (p = 0.31) was found when the durations of the first and second CR were compared in patients with a second relapse. Patients with long-lasting remissions and long-term survivors after second CR are characterized by a first CR duration of > 12 months and favorable or normal cytogenetics. The type of salvage treatment seems to be less important for achievement of long-term remission, but it is probably important to administer consolidation chemotherapy after second CR. Other so-far ill-defined factors may be responsible for the suppression of the leukemic clone in patients with long-lasting remissions following chemotherapy for relapse after second CR.

Adolescent↗
PubMed1996

Spontaneous remission of acute myeloid leukemia after infection and blood transfusion associated with hypergammaglobulinaemia.

Spontaneous remissions of acute myeloid leukemia (AML) have been documented in association with infection as well as blood transfusions. Activation of the immune system including an increased number of NK cells and cytokine release have been implicated in the mechanism of this phenomenon. We have observed spontaneous remissions in two patients with AML (one with a t(8;21)-positive M2, one with M5b), both occurring after infection and blood transfusions. The bone marrow showed a reduction of blast cells from 65% to 2% or 40% to 1%, respectively. Remission was accompanied by a marked polyclonal hypergammaglobulinemia in both cases (IgG values of 6420 and 2160 mg/dl, IgA of 802 and 811 mg/dl, respectively). A concomitant increase in bone marrow plasma cells was observed in both patients. Reduction of AML1/ETO PCR positivity from one-step to two-step PCR (approximately 100-fold) was documented in the patient with a t(8;21), while a regression of lymph node and skin leukemic infiltrations occurred in the patient with M5b. One patient relapsed after 4 months, at a time when his serum immunoglobulin levels had markedly decreased. The other patient is in continuous remission after 14 months. These cases suggest a potential role for a humoral immune response in the mechanism of spontaneous remission.

Acute Disease↗