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Biomedical subjects

K A Bauer

Publications and source records attributed to K A Bauer.

At least 37 records · Page 2Linked to original sources
PubMed2001

The thrombophilias: well-defined risk factors with uncertain therapeutic implications.

Discovery of the factor V Leiden and prothrombin G20210A mutations has greatly increased the percentage of patients in whom venous thrombosis can be attributed to hereditary thrombophilia. The first step in the diagnostic approach to all patients with venous thrombosis consists of a careful history and physical examination combined with routine laboratory testing to characterize the severity of the thrombotic condition and determine the presence of any of the acquired causes of hypercoagulability. The second step is to consider screening for the causes of hereditary and acquired thrombophilia in selected subsets of patients. The selection of patients for testing, the choice of tests to perform, and the timing of the testing are important and challenging issues to consider. Routine testing would be warranted if the identification of abnormalities led to an alteration in the type or duration of initial anticoagulant therapy or the use of long-term prophylactic anticoagulation. The available data, however, do not yet indicate that most patients with defined thrombophilic states should be managed any differently than patients without identifiable abnormalities. On the basis of relative prevalences of the various thrombophilias, patients can be classified as "strongly" or "weakly" thrombophilic depending on their thrombotic histories. Management considerations and guidelines are offered for patients who are found to have one or more defined abnormalities, hereditary or otherwise. The future identification of additional laboratory abnormalities predisposing patients to thrombosis, coupled with prospective clinical trials, should enable us to better identify patients at high risk for recurrence who will benefit from prolonged anticoagulant prophylaxis.

Anticoagulants↗
PubMed2001

Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects.

BACKGROUND: In view of the central role of the tissue factor-factor VIIa pathway in the initiation of blood coagulation, novel therapeutic strategies aimed at inhibiting this catalytic complex are currently being evaluated. A limitation of this new class of anticoagulants may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs. The aim of this study was to investigate the in vivo potential of recombinant factor VIIa (rVIIa) to induce thrombin generation in healthy subjects pretreated with recombinant nematode anticoagulant protein c2, a specific inhibitor of the tissue factor-factor VIIa complex, in a double-blind randomized crossover study. METHODS AND RESULTS: Administration of nematode anticoagulant protein c2 (3.5 microgram/kg) caused a prolongation of the prothrombin time from 13.7+/-0.6 to 16.9+/-1.2 seconds. The subsequent injection of rVIIa (90 microgram/kg) resulted in an immediate and complete correction of the prothrombin time and a marked generation of thrombin, reflected by increased levels of prothrombin activation fragment F1+2 and thrombin-antithrombin complexes from 0.75+/-0.64 to 3.29+/-6.3 nmol/L and from 2.4+/-0.6 to 10.7+/-3.9 microgram/mL, respectively. Factor X and IX activation peptides showed a 3.5-fold and a 3.8-fold increase, respectively, after the administration of rVIIa in the presence of nematode anticoagulant protein c2. CONCLUSIONS: During treatment with an inhibitor of the tissue factor-factor VIIa complex, the infusion of rVIIa resulted in thrombin generation. Our results indicate that rVIIa may be a good candidate as an antidote for inhibitors of tissue factor.

Adult↗
PubMed2001

Abnormal secretion and function of recombinant human factor VII as the result of modification to a calcium binding site caused by a 15-base pair insertion in the F7 gene.

A case of a novel mutation in the F7 gene that results in factor VII coagulant activity (VII:c) of less than 1% and VII antigen (VII:Ag) levels of 10% is presented. DNA analysis revealed a homozygous 15-base pair (bp) in-frame insertion-type mutation at nucleotide 10554. This insertion consisted of a duplication of residues leucine (L)213 to aspartic acid (D)217 (leucine, serine, glutamic acid, histidine, and aspartic acid), probably arising by slipped mispairing between 2 copies of a direct repeat (GCGAGCACGAC) separated by 4 bp. Molecular graphic analyses showed that the insertion is located at the surface of the catalytic domain in an exposed loop stabilized by extensive salt-bridge and hydrogen bond formation at which the calcium binding site is located. The mutation probably interferes with protein folding during VII biosynthesis and/or diminishes functional activity through the loss of calcium binding. In vitro expression studies demonstrated that the levels of VII:Ag in lysates of cells transfected with wild type VII (VIIWT) were equivalent to those with mutant type VII (VIIMT), but the level of secreted VIIMT was 5% to 10% that of VIIWT. Pulse chase studies demonstrated that VIIMT did not accumulate intracellularly, and studies with inhibitors of protein degradation showed that recombinant VIIMT was partially degraded in the pre-Golgi compartment. Accordingly, only small amounts of VIIMT with undetectable procoagulant activity were secreted into conditioned media. These results demonstrate that a combination of secretion and functional defects is the mechanism whereby this insertion causes VII deficiency.

Base Pair Mismatch↗
PubMed2001

Automated detection of the G20210A prothrombin mutation using the LCx microparticle enzyme immunoassay.

BACKGROUND: The prothrombin mutation, a G/A transition at position 20210 in the 3' untranslated region of the prothrombin gene, is associated with an increased risk of deep venous thrombosis and obstetrical complications. Several methods have been developed to detect the mutation; however, given the increased demand for this test in risk factor assessment, the development of simple and efficient screening methods has become necessary. METHODS: We have used a rapid, sensitive, and precise method developed by Abbott Laboratories to detect the prothrombin mutation. The method employs a polymerase chain reaction (PCR) amplification and the Abbot LCx microparticle enzyme immunoassay (MEIA) for detection. This method is able to detect and identify both homozygous and heterozygous genotypes. RESULTS: Two hundred ninety-six patients with a history of deep venous thrombosis, pulmonary embolism, preeclampsia, or cardiovascular disease and 163 control patients were included in this study. The prevalence of the mutation was 5.74% in the high-risk group and 3.06% in the control group. There was complete agreement between the results from the MEIA detection with those obtained using other detection methodologies, namely standard PCR and restriction fragment length polymorphism (RFLP) analysis. CONCLUSIONS: The MEIA detection method of the prothrombin mutation represents a simple, fast, and reliable alternative to standard methods of detection and is well suited for use in routine clinical laboratories. The results of our study confirm others' studies showing a greater incidence of G20210A prothrombin gene mutation in patients with an increased risk of venous thrombosis and pulmonary embolism as well as patients with cardiovascular disease and pregnant women with preeclampsia. It reinforces the necessity of including the screening for prothrombin mutation in populations at risk.

3' Untranslated Regions↗
PubMed2001

Hemostatic markers and prognosis in ischemic heart disease.

Failure of traditional risk factors in identifying patients who develop a cardiac event, has led investigators to focus on other factors involved in precipitating cardiac events. As acute or subacute thrombosis is the major complication of atherosclerotic plaque rupture, attention has been dedicated to prothrombotic markers as possible risk factors. Recently, the role of new laboratory markers in predicting the risk of cardiac events has been evaluated in large epidemiological studies. The results of these studies as well as the value and applicability of new prothrombotic markers in the clinical practice are discussed.

Biomarkers↗
PubMed2000

A new mutation in the HNF4 binding region of the factor VII promoter in a patient with severe factor VII deficiency.

Investigation of the molecular basis of a severe factor VII (fVII) deficiency revealed compound heterozygosity in the fVII gene. On the paternal allele the patient had 3 structural gene abnormalities frequently associated with fVII deficiency. A new mutation, a C to T transition at position -55 relative to the translational start site, was found on the maternal allele. The study demonstrates that this mutation partially impeded binding of the transcriptional activator, hepatic nuclear factor 4, to the fVII promoter while greatly reducing reporter gene expression in hepatic cells. (Blood. 2000;96:4370-4372)

Adult↗
PubMed2000

Comparison of novel hemostatic factors and conventional risk factors for prediction of coronary heart disease.

BACKGROUND: This study sought to assess whether novel markers of hemostatic activity are predictive of coronary heart disease (CHD) and improve risk assessment. METHODS AND RESULTS: Conventional CHD risk factors, the activation peptides of factor IX and factor X, factor VII activity and antigen, activated factor XII, prothrombin fragment 1+2, fibrinopeptide A, and fibrinogen were measured in 1153 men aged 50 to 61 years who were free of myocardial infarction at recruitment. Activated factor VII (VIIa) was measured in 829 men. During 7.8 years of follow-up, 104 had a CHD event. Baseline status was related to outcome by logistic regression by using a modified nested case-control design. Screening performance was judged from receiver operating characteristic curves. A high activated factor XII was associated with increased CHD risk, but low levels were not protective. Plasma VIIa and factor X activation peptide were independently and inversely related to risk. Plasma factor IX activation peptide and fibrinogen were positively associated with risk, but the relations were no longer statistically significant after adjustment for other factors, including VIIa and apoA-I. Other hemostatic markers were not associated with CHD risk. CONCLUSIONS: Hemostatic status did not add significant predictive power to that provided by conventional CHD risk factors yet was able to substitute effectively for these factors.

Biomarkers↗
PubMed2000

Recombinant factor VIIa for the treatment of congenital factor VII deficiency.

Factor VII deficiency is a rare autosomal bleeding disorder with a highly variable hemorrhagic predisposition. Severe bleeding, including hemarthroses, may be encountered when plasma factor VII levels are below 1%. Patients have prolonged prothrombin times, and the final diagnosis is established by quantitative factor VII assays. Some patients have true deficiencies, that is, very low factor VII activity and low factor VII antigen (cross-reacting material) levels (CRM-); others have normal antigen levels but low activity (CRM+). Still others have reduced antigen levels (CRMR). There is a rather poor correlation between clinical symptoms and factor VII activity levels in plasma. Treatment of these patients consists of fresh frozen plasma, prothrombin complex concentrates, or factor VII concentrates. Recombinant activated factor VII (rFVIIa) is a very useful alternative, and several patients have been treated successfully. Because of the short half-life of factor VIIa, repeated doses have to be administered, and continuous infusion may be even better. Antibodies to factor VII have been reported but seem to be rather rare. From the available data it appears that rFVIIa is a safe and effective treatment modality for patients with congenital factor VII deficiency.

Factor VII↗
PubMed2000

Activation of clotting factors XI and IX in patients with acute myocardial infarction.

In acute coronary events, plaque rupture and the subsequent formation of the catalytic tissue factor-factor VIIa complex is considered to initiate coagulation. It is unknown whether clotting factors XI and IX are activated in acute coronary events. Therefore, we prospectively investigated the activation of clotting factors XI and IX as well as activation of the contact system and the common pathway in 50 patients with acute myocardial infarction (AMI), in 50 patients with unstable angina pectoris (UAP), and in 50 patients with stable angina pectoris (SAP). Factor XIa-C1 inhibitor complexes, which reflect acute activation of factor XI, were detected in 24% of the patients with AMI, 8% of the patients with UAP, and 4% of the patients with SAP (P<0.05), whereas factor XIa-alpha(1)-antitrypsin complexes, which reflect chronic activation, were observed equally in all 3 study groups. Factor IX peptide levels were significantly higher in the patients with AMI and UAP compared with the patients with SAP (P<0.01). No differences regarding markers of the common pathway were demonstrated. Fibrinopeptide A levels were elevated in patients with AMI compared with patients with UAP and those with SAP (P<0.01). Factor XIIa- or kallikrein-C1 inhibitor complexes were not increased. In conclusion, this is the first demonstration of the activation of clotting factors XI and IX in patients with acute coronary syndromes. Because these clotting factors are considered to be important for continuous thrombin generation and clot stability, their activation might have clinical and therapeutic consequences.

Angina Pectoris↗
PubMed2000

In vivo thrombin generation and activity during and after intravenous infusion of heparin or recombinant hirudin in patients with unstable angina pectoris.

In patients with unstable angina, intravenous heparin reduces thrombin activity but does not influence thrombin generation. Recombinant hirudin, a direct thrombin inhibitor, may be more effective in inhibiting both thrombin generation and activity. We measured the plasma levels of prothrombin fragment 1+2 (a marker of thrombin generation) and fibrinopeptide A (a marker of thrombin activity) in 67 patients with unstable angina enrolled in the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) IIb trial who were receiving either recombinant hirudin (31 patients) or heparin (36 patients). Blood samples were obtained at baseline (before any treatment), after 3 to 5 days of study drug infusion (immediately before discontinuation), and 1 month later. In the patients receiving recombinant hirudin, the prothrombin fragment 1+2 levels measured immediately before drug discontinuation were significantly lower than at baseline (P:=0.0014), whereas they had not changed in the patients receiving heparin; at this time point, the difference between patients receiving hirudin and those receiving heparin was statistically significant (P:=0.032). One month later, the prothrombin fragment 1+2 levels in both groups were similarly persistently high and did not differ from baseline. Fibrinopeptide A plasma levels at the end of infusion were significantly lower than at baseline in both treatment groups (P:=0. 0005 for hirudin and P:=0.042 for heparin) and remained lower after 1 month (P:=0.0001 for both hirudin and heparin). The fibrinopeptide A plasma levels were not different between patients treated with hirudin versus heparin at baseline, at the end of infusion, and after 1 month. Thus, in patients with unstable angina, in vivo thrombin generation and activity are reduced during intravenous infusion of recombinant hirudin. However, the inhibition of thrombin generation is not sustained, and after 1 month, the majority of patients have biochemical signs of increased thrombin generation.

Aged↗
PubMed2000

The ethical and social dimensions of home-based telemedicine.

The growth of home-based telemedicine invites a discussion about the ethical implications of this technology for the traditional goals and moral ideals of medical practice. To this end, I examine the normative connections between home-based telemedicine and the following: (1) health care justice, (2) quality of life for patients and family caregivers, and (3) provider-patient relationships.

Caregivers↗
PubMed2000

The G20210A prothrombin polymorphism is not associated with increased thromboembolic risk in a large protein C deficient kindred.

Likelihood analysis was used to test the effect of the G20210A prothrombin mutation and the His107Pro protein C mutation (resulting from a C insertion) on thrombosis status and prothrombin level in a large kindred of French Canadian descent with type I protein C deficiency. Genotypes were available on 279 pedigree members or their spouses. Of this total, 36 pedigree members were heterozygous for the G20210A variant and one pedigree member was homozygous for G20210A, while 64 were heterozygous for the His107Pro protein C mutation. The factor V Leiden mutation (Arg506Gln) was observed in only one of 181 tested family members. Objectively verified thrombosis was present in 26 of the 279 pedigree members. Thrombosis was suspected in an additional 19 pedigree members. The transmission disequilibrium test of Spielman, 1996, as extended to pedigrees, was used to test for excess transmission of G20210A or His107Pro to thrombosis cases, with transmission of 0.5 specifying no effect. Although the His107Pro mutation was over transmitted (0.837 +/- 0.075 p <0.001) to thrombosis cases in this pedigree, the G20210A variant was not (0.491 +/- 0.130 NS). Measured genotype analysis was used to examine a total of 184 individuals for the relationship between prothrombin level and both the G20210A variant and thrombosis. The G20210A variant increased prothrombin level from 97 +/- 2% to 124 +/- 4% (p <0.0001), but thrombosis status was not associated with any additional increase in prothrombin level. Thus, in a large thrombophilic, protein C deficient kindred, with the G20210A variant present in a proportion (13%) far higher than the general Caucasian population (approximately 2%), neither the presence of the variant nor the plasma concentration of prothrombin were associated with increased risk for thrombosis. These findings contrast with those of others who have established the G20210A variant as a thrombophilic risk factor; and emphasize the complex nature of the multigenic pathogenesis of thrombophilia.

Female↗
PubMed2000

Prothrombin activation is increased among asymptomatic carriers of the prothrombin G20210A and factor V Arg506Gln mutations.

The risk of venous thrombosis is increased in individuals who carry specific genetic abnormalities in blood coagulation proteins. Among Caucasians, the prothrombin G20210A and factor V Arg506Gln (FV R506Q) mutations are the most prevalent defects identified to date. We evaluated their influence on markers of coagulation activation among participants in the Second Northwick Park Heart Study, which recruited healthy men (aged 50-61 years) from nine general medical practices in England and Wales. They were free of clinical vascular disease and malignancy at the time of recruitment. Genotypes for the two mutations were analyzed using microplate array diagonal gel electrophoresis, and coagulation markers (factor XIIa; activation peptides of factor IX, factor X, and prothrombin; fibrinopeptide A) were measured by immunoassay. Factor VII coagulant activity and factor VIIa levels were determined by a functional clotting assay. Among 1548 men genotyped for both mutations, 28 (1.8%) and 52 (3.4%) were heterozygous for prothrombin G202 IOA and FV R506Q, respectively. The only coagulation marker that was significantly associated with the two mutations was prothrombin activation fragment FI+2 [mean +/- SD, 0.88 +/- 0.32 nmol/L in men with prothrombin G20210A (p = 0.002) and 0.89 +/- 0.30 in men with FV R506Q (p = 0.0001) versus 0.72 +/- 0.24 among non-carriers for either mutationl. This data provides conclusive evidence that heterozygosity for the prothrombin G20210A as well as the FV R506Q mutations in the general population leads to an increased rate of prothrombin activation in vivo.

Blood Coagulation Factors↗
PubMed1999

Two multiplex PCR-based DNA assays for the thrombosis risk factors prothrombin G20210A and coagulation factor V G1691A polymorphisms.

Two coagulation factor polymorphisms, G1691A in the factor V gene and G20210A in the prothrombin gene, are currently the most common known genetic risk factors for venous thrombosis in caucasian populations. Experimental conditions that permit simultaneous determination of these two polymorphisms using PCR-based DNA assays with the restriction enzyme, Hind III, were developed. Moreover, novel PCR-based DNA assays were established using primers that introduce specific cleavage sequences which then permit the simultaneous determination of these polymorphisms using Sac I restriction digestion analysis. Multiplex PCR-based DNA assays were used to analyze a family with a history of venous thrombosis in which these polymorphisms were both present and the results confirm the interesting variability of these genetic risk factors among family members who are symptomatic.

Biological Assay↗
PubMed1999

Characterization of two naturally occurring mutations in the second epidermal growth factor-like domain of factor VII.

We investigated the mechanisms responsible for severe factor VII (FVII) deficiency in homozygous Italian patients with either Gly97Cys or Gln100Arg mutations in the second epidermal growth factor domain of FVII. Transient expression of complementary DNA coding for the mutations in COS-1 cells showed impaired secretion of the mutant molecules. Using stably transfected Chinese hamster ovary (CHO) cells, we performed pulse-chase labeling studies, immunohistochemistry, and experiments with inhibitors of protein degradation, showing that FVII-Cys97 did not accumulate intracellularly but was degraded in a pre-Golgi, nonlysosomal compartment by a cysteine protease. In stably transfected CHO cells expressing FVII-Arg100, the level of intracellular FVII was not increased by several inhibitors of protein degradation, but FVII-Arg100 was retained in the endoplasmic reticulum for a longer period of time than wild-type FVII. FVII-Arg100 had a lower apparent molecular weight than did wild-type FVII under nondenaturing conditions, which is attributable to misfolding due to abnormal disulfide bond formation.

Animals↗