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B Wiman

Publications and source records attributed to B Wiman.

At least 55 records · Page 3Linked to original sources
PubMed1994

Soluble fibrin: a predictor for the development and outcome of multiple organ failure.

UNLABELLED: According to our hypothesis ICU patients with signs of early hypercoagulation should develop more organ system failures that result in higher mortality rates and longer treatment periods. Routine coagulation tests are unreliable for measuring early hypercoagulation. METHODS: Soluble fibrin (SF), reflecting hypercoagulation, was assessed at an early stage in 101 ICU patients. A spectrophotometric method using chromogenic peptide substrates was employed. The patients were divided into four groups, depending on the patient's highest level of SF within the first week after admission: Group I (21 patients), SF < 15 nmol/L (reference level); Group II (27 patients), SF 15-29 nmol/L; Group III (26 patients), SF 30-50 nmol/L and Group IV (27 patients), SF > 50 nmol/L. The number of secondary failing organ systems and the ventilator time, ICU time and mortality rates were recorded. RESULTS: There was a significant increase in the number of secondary failing organ systems (P < 0.0001) and a significantly increased mortality for the groups with higher SF (P = 0.01). There was a mean of 0.6, 1.3, 2.4, and 3.4 failing organs and a mortality of 14%, 22%, 30%, and 46% in the respective groups. The ventilator time and the ICU time were longest in Group III, but again shorter for Group IV (with the highest mortality). The mean ventilator times were 2.7, 6.4, 8.4, and 5.9 days and the mean ICU times were 4.1, 8.6, 10.3, and 7.3 days in the respective groups. Thirteen patients with SF > 100 nmol/L had a mean of 4.2 failing organ systems and an 85% mortality. CONCLUSION: Soluble fibrin, a marker of hypercoagulation, seems to predict organ system failure and outcome in ICU patients.

Critical Care↗
PubMed1994

Binding of tissue-type plasminogen activator (t-PA) to Neisseria meningitidis and Haemophilus influenzae.

Forty-nine bacterial strains representing five species known to interact with human plasminogen were tested for the ability to bind the two major human plasminogen activators, t-PA and urokinase. The bacterial species tested included Haemophilus influenzae, Neisseria meningitidis, Streptococcus pyogenes, Streptococcus equisimilis and human group G streptococci. All N. meningitidis and 11 of 14 H. influenzae strains displayed substantial binding of t-PA with values in the range of 20-46%. On the contrary, none of the streptococcal strains bound significant amounts of tPA. With urokinase no binding could be found for any of the bacterial species tested. Scatchard analysis with a selected H. influenzae strain (HI23354) demonstrated 10,000 receptors per bacterium for t-PA with a Kd value of about 20 nmol l-1. The corresponding values with a selected N. meningitidis strain (Mo 52) was 8500 receptors per bacterium and 70 nmol l-1. t-PA binding could be reduced about 40% by the addition of 10 mmol l-1 of the lysine analogue epsilon-aminocaproic acd (EACA) whereas no inhibitory effect could be demonstrated with arginine. Addition of 2 mumol l-1 of plasminogen which is enough to occupy all bacterial sites for plasminogen did not interfere with the t-PA binding, suggesting that the receptors for t-PA and plasminogen are distinct. Using very high plasminogen concentrations however, t-PA binding could be reduced by about 50% possibly due to an interaction between t-PA and plasminogen in the fluid phase. Our results demonstrate the occurrence of a previously unknown type of bacterial receptor that is capable of specifically binding t-PA.

Aminocaproic Acid↗
PubMed1994

Haemostatic factors and inhibitors and coronary artery bypass grafting: preoperative alterations and relations to graft occlusion.

Graft closure remains a major problem after coronary artery bypass surgery. While a number of graft characteristics influencing the risk of occlusion have been defined, the role of haemostatic factors and inhibitors has not been studied in detail. The present study examined the time course of changes in blood coagulation and fibrinolytic function after coronary artery bypass grafting in 20 consecutive patients. Pre- and postoperative determinations of haemostatic factors and inhibitors were also related to the presence of graft occlusion assessed by angiography at three months after surgery. A broad panel of haemostatic tests was used preoperatively, on the first, third and eight postoperative days, and at three months after surgery. A particular emphasis was placed on fibrinogen, factor VII activity, von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1) activity, anticoagulant proteins C and S, thrombin-antithrombin complex and D-dimer. A marked activation of the coagulation cascade was noted postoperatively along with enhanced degradation of cross-linked fibrin. The degree of activation of blood coagulation and fibrinolysis differed widely between individuals and appeared to relate only partly to the acute phase reaction produced by the surgical trauma. Preoperative values of haemostatic factors and inhibitors showed fairly weak associations with the levels of postoperative determinations.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute-Phase Proteins↗
PubMed1993

The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells.

We have detected a common (allele frequency 0.53/0.47) single base pair insertion/deletion polymorphism 675 base pairs upstream from the start of transcription of the plasminogen activator inhibitor-1 (PAI-1) gene, using the chemical cleavage mismatch analysis. "Band shift assays" suggest that the allele with the single base pair insertion contains an additional protein binding site which is not present in the del allele. Competition experiments confirmed that the binding was specific to the sequence of the ins allele and suggest that proteins bound to this site may be NF-kB-like proteins. Analysis of chloramphenicol acetyltransferase (CAT) mRNA produced by constructs containing the PAI-1 promoter (-805 to +83) showed that the deletion allele produced six times more mRNA than the insertion allele in response to interleukin-1 (p < 0.001). In a sample of 107 young patients with previous myocardial infarction and 95 healthy population-based subjects, the del allele was associated with increased PAI-1 levels, 21% higher than the sample mean in the del homozygotes (p < 0.05). This study also suggested that individuals homozygous for the del allele may have an altered response to the acute phase stimulus. Taken together these results suggest that the insertion/deletion polymorphism in the PAI-1 promoter is of functional importance in regulating the expression of the PAI-1 gene.

Adult↗
PubMed1993

Relationship between plasma plasminogen activator inhibitor-1 activity and VLDL triglyceride concentration, insulin levels and insulin sensitivity: studies in randomly selected normo- and hypertriglyceridaemic men.

Impaired fibrinolytic function secondary to elevated plasma plasminogen activator inhibitor-1 activity, hypertriglyceridaemia and hyperinsulinaemia are frequent findings in patients with coronary heart disease. It has been debated whether VLDL or insulin is the major regulator of plasma plasminogen activator inhibitor-1 activity. This study examines the relationships between plasma plasminogen activator inhibitor-1 activity and VLDL triglyceride concentration, fasting and post-oral glucose load insulin levels and insulin sensitivity, as estimated by the minimal model method. Subjects studied were randomly selected hypertriglyceridaemic (n = 65) and age-matched normotriglyceridaemic (n = 61) men, aged 40-50 years, recruited in a population survey. Plasma plasminogen activator inhibitor-1 activity was higher in the hypertriglyceridaemic than in the normotriglyceridaemic group (21 +/- 14 vs 10 +/- 8 mU/l; p < 0.01). The hypertriglyceridaemic group had higher serum insulin, basal as well as 2 h after intake of the oral glucose load, and a lower insulin sensitivity index. In univariate analysis, plasma plasminogen activator inhibitor-1 activity correlated positively with VLDL triglycerides in both the hyper- and normotriglyceridaemic groups (r = 0.43 r = 0.60, respectively) and negatively with the insulin sensitivity index (r = -0.35 r = -0.44, respectively). In multivariate analysis, VLDL triglyceride levels were found to be independently related to plasma plasminogen activator inhibitor-1 activity in both groups, whereas insulin sensitivity/serum insulin levels were not. An unexpected finding was that the serum activity of the enzyme gamma glutamyl transpeptidase appeared to influence the relationships for plasma plasminogen activator inhibitor-1 in the hypertriglyceridaemic group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Laboratory methods for detecting disseminated intravascular coagulation (DIC): new aspects.

The objective was to diagnose a hypercoagulative state or "pre-DIC" with new laboratory tests. APACHE II score was used as a measure of primary illness. Ventilator time was used as a reflexion of secondary complications. Twenty-three ICU patients were divided into two groups depending on time on the ventilator: Group 1 > 7 days and Group II < or = 7 days. If, after admittance patients deteriorated or complications occurred, new quantitative coagulation tests were done: soluble fibrin, prothrombin fragment 1 + 2, thrombin-antithrombin complex, D-dimer and elastase. We found a positive correlation between SF levels, the APACHE II score and the ventilator time. Diagnostic efficacy for SF was 87%, sensitivity 91%, specificity 83%, the predictive value of a positive result was 87% and the predictive value of a negative result 91%. The levels of the other new tests were also generally higher in the clinically worse group, although not significantly. Prothrombin complex, APTT, platelet count and AT III were pathologic to the same extent in both groups. The patients who developed most secondary complications, resulting in longer ventilator treatment (Group I), were also hypercoagulative. Soluble fibrin, in particular, seems to be valuable in the diagnosis of "pre-DIC" and possibly of predictive value for organ system complications.

Adult↗
PubMed1992

Genetic factors determining thrombosis and fibrinolysis.

Raised plasma levels of fibrinogen, factor VIIc, and plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of ischemic heart disease. Levels of these proteins are determined in part by environmental influences such as smoking and dietary fat intake. However, genetic variation explains much of the interindividual variation in plasma levels of these proteins not accounted for by environmental factors. We previously investigated the DNA variation at the fibrinogen gene locus and showed that BclI restriction fragment length polymorphism (RFLP) of the beta-fibrinogen gene is associated with between-person differences in plasma fibrinogen levels. This RFLP is unlikely to be the functional base change itself, since it lies downstream of the gene. The rate-limiting step in the production of the mature fibrinogen molecule in the human hepatoma cell-line HepG2 is the synthesis of the beta-polypeptide chain, which in turn is influenced by the amount of messenger (mRNA) available. One possibility is that BclI RFLP is in linkage disequilibrium with a base change in the region of the beta-gene controlling synthesis of its mRNA and ultimately of fibrinogen protein. We identified a base change in the 5'-flanking region of the beta-fibrinogen gene that is in linkage disequilibrium with the BclI RFLP, that is associated with plasma fibrinogen levels, and that may be involved in control of fibrinogen gene expression. For the factor VII gene, we identified a polymorphism, detected after Msp I digestion of polymerase chain reaction (PCR)-amplified genomic DNA, that is strongly associated with factor VII coagulant activity (factor VIIc). The base change that creates the Msp I polymorphism is a G to A substitution, leading to the replacement of arginine (Arg) with glutamine (Gln) in the protein product of the M2 allele. In a sample of 284 men from the United Kingdom the frequency of the Gln allele (M2 loss of cutting site) is 0.1, and individuals of genotype Arg/Gln have factor VIIc levels 22% below the sample mean. In this sample, the Msp I genotype was found to be the strongest predictor of factor VIIc, accounting for 20.2% of the variance, with cholesterol accounting for an additional 3.5%. Three individuals homozygous for the Gln allele had both low factor VIIc and low factor VII protein concentrations. The conformation of the factor VII Gln may be different from that of the Arg protein, affecting its intracellular processing, secretion, turnover in plasma, or activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Factor VIII↗
PubMed1992

Disseminated intravascular coagulation in neurosurgical patients: diagnosis by new laboratory methods.

Disseminated intravascular coagulation (DIC) constitutes a part of the multiple organ failure (MOF) syndrome seen with such disorders as trauma and sepsis. Early detection of increased coagulation and fibrinolytic activity is important. The dynamic changes in some markers for early detection of the activation of these cascade systems are presented in relation to two patients with brain trauma. The clinical status and the severity of the disease were assessed by an established scoring method (APACHE II). The coagulation activation was noted by the appearance of increased end products of the coagulation cascade, such as soluble fibrin, thrombin-antithrombin complex, and prothrombin fragment 1 + 2. Fibrinolytic activation and an increased secondary inhibition of fibrinolysis were detected by increased levels of D-dimer and plasminogen activator inhibitor-1. Leukocyte activation was indicated by a rise in elastase. The laboratory results normalized with clinical improvement. These new methods seem to detect DIC earlier than traditional methods and may also be of value for monitoring treatment.

Journal Article↗
PubMed1992

Two types of receptors for human plasminogen on group G streptococci.

To investigate the nature of plasminogen binding to streptococci, strains selected for high reactivity with human plasminogen were examined for binding pattern against a panel of plasminogen fragments. The strains included human isolates of groups A, C and G as well as bovine isolates of group G. All strains reacted substantially with the plasminogen fragment kringle 1-3. Using the miniplasminogen fragment (kringle 5 and the B chain) a small but reproducible uptake was detected for human group G strains but not for group A or C strains. The group G strains of bovine origin on the other hand demonstrated high uptake of miniplasminogen, suggesting the possibility of an alternative plasminogen receptor for this species. This interpretation was supported by blocking experiments with the lysine analogue EACA where low concentrations (1 mM) completely blocked plasminogen binding to human streptococci, whereas a 100-fold higher concentration was needed for bovine group G strains. Scatchard plots with human isolates resulted in straight lines and Kd values were generally in the range of 20-80 nM. The number of receptors was estimated to be 45,000 for a selected group A strain and about 10,000 for the selected group C and G strains. Scatchard analysis with bovine group G isolates on the other hand revealed a two phase interaction, supporting the assumption of two different receptor structures on these strains. Kd for the first phase was estimated to be about 20 nM (10,000-20,000 receptors per bacterium), which was similar to the human strains, whereas the second phase was in the range of 400-500 nM (50,000 and 150,000 receptors per bacterium with two selected strains). Scatchard plots with the miniplasminogen fragment as ligand mimicked the phase two reaction with plasminogen, supporting the concept that this reaction represents a new and not previously described receptor. Both the receptor reacting with the kringle 1-3 portion and the one reacting with the miniplasminogen portion bound plasmin and plasminogen with similar affinity.

Aprotinin↗
PubMed1991

[New methods accelerate the development of thrombolytic agents].

Owing to the possible involvement of impaired fibrinolytic function in venous and arterial thrombotic disorders, and the benefit of thrombolytic treatment in the acute stage of myocardial infarction, the fibrinolytic system has attracted increasing interest. In this brief review are discussed recent advances in our knowledge of the regulation of fibrinolysis and the effect in thrombolytic disorders of impaired tissue plasminogen activator release and increased concentrations of the endothelial cell-related plasminogen activator inhibitor. PAI-1. Also discussed are the molecular basis of effective and specific thrombolytic treatment and progress in the search for and development of new, primarily recombinant, fibrin-specific plasminogen activators.

Fibrinolysis↗
PubMed1990

Correlations between fibrinolytic function and acute myocardial infarction.

The diurnal variation of tissue plasminogen activator and plasminogen activator inhibitor--2 important factors in regulation of fibrinolysis--is well established, but its clinical implications are not yet fully understood. Fibrinolytic function was measured in a group of 133 patients less than 45 years of age, 3 months after they presented with myocardial infarction, and they were compared with an equal group of carefully matched control subjects. A sub-sample of 71 patients and 50 control subjects was examined 3 years later. Tissue plasminogen activator inhibitor plasma levels were higher in patients versus control subjects at 3 months and at 3 years after myocardial infarction, with a high degree of correlation between the 2 determinations (r = 0.87). Of all hemostatic parameters studied, only low tissue plasminogen activator activity and increased tissue plasminogen activator inhibitor levels were significantly different between patients with and without recurrent infarction during the 3-year period. In those patients with a second infarction greater than 3 years later, however, tissue plasminogen activator inhibitor concentration was not significantly related to reinfarction.

Adult↗
PubMed1990

Complex formation between plasminogen activator inhibitor 1 and vitronectin in purified systems and in plasma.

Functionally active PAI-1 is bound to a discrete binding or carrier protein in plasma, which was recently identified as vitronectin. In the present study, the interaction between PAI-1 and vitronectin has been studied in purified systems and in plasma by agarose gel electrophoresis using non-denaturing conditions and by crossed immunoelectrophoresis using an antiserum produced towards purified PAI-1/vitronectin complex. Both methods revealed a clearly distinguishable complex with electrophoretic mobility in between the parent molecules. Virtually all of the purified vitronectin, which did not contain any appreciable amounts of polymerized material, and almost all of the vitronectin in plasma, had the capacity to form a complex with PAI-1. The results suggested a stoichiometry of 1:1 as the most likely ratio between the two molecules in the complex. In contrast to functionally active PAI-1, latent or chloramine T-inactivated PAI-1 did not form such a complex with vitronectin.

Animals↗
PubMed1990

Influence of metoprolol treatment on sympatho-adrenal activation of fibrinolysis.

The effects of mental stress (a colour word conflict test, CWT) and adrenaline infusions (0.1 and 0.4 nmol kg-1 min-1) on t-PA activity, t-PA antigen, PAI-1 activity and PAI-1 antigen were studied in 18 healthy male volunteers. Furthermore, the effects of metoprolol (200 mg/day during 1 week) or placebo (double-blind cross-over study) on fibrinolytic responses to sympatho-adrenal activation, and relationships between fibrinolysis and blood lipids were investigated. Low and high dose adrenaline infusions yielding plasma adrenaline levels of 0.9 +/- 0.1 and 3.4 +/- 0.4 nmol/l, respectively, dose-dependently increased t-PA levels with a concomitant decrease in PAI-1 levels. A similar, but weaker, fibrinolytic response seemed to occur during CWT, when plasma adrenaline levels were only moderately increased (to 0.4 +/- 0.1 nmol/l). Metoprolol treatment did not influence the resting levels of the fibrinolytic variables studied, but tended to enhance the t-PA response to CWT and further reduce PAI-1 during adrenaline infusion. Metoprolol treatment was not accompanied by any rise in PAI-1 levels despite drug induced elevations of triglyceride levels. Thus, the present study shows that sympatho-adrenal activation increases fibrinolytic activity in vivo and that metoprolol treatment may have a favourable influence on this activity.

Adrenal Glands↗
PubMed1990

The mechanism of the reaction between human plasminogen-activator inhibitor 1 and tissue plasminogen activator.

The structural events taking place during the reaction between PAI-1 (plasminogen-activator inhibitor 1) and the plasminogen activators sc-tPA (single-chain tissue plasminogen activator) and tc-tPA (two-chain tissue plasminogen activator) were studied. Complexes were formed by mixing sc-tPA or tc-tPA with PAI-1 in slight excess (on an activity basis). The complexes were purified from excess PAI-1 by affinity chromatography on fibrin-Sepharose. Examination of the purified complexes by SDS/polyacrylamide-gel electrophoresis (SDS/PAGE) and N-terminal amino acid sequence analysis demonstrated that a stoichiometric 1:1 complex is formed between PAI-1 and both forms of tPA. Data obtained from both complexes revealed the amino acid sequences of the parent molecules and, in addition, a new sequence: Met-Ala-Pro-Glu-Glu-. This sequence is found in the C-terminal portion of the intact PAI-1 molecule and thus locates the reactive centre of PAI-1 to Arg346-Met347. The proteolytic activity of sc-tPA is demonstrated by its capacity to cleave the 'bait' peptide bond in PAI-1. The complexes were inactive and dissociated slowly at physiological pH and ionic strength, but rapidly in aq. NH3 (0.1 mol/l). Amidolytic tPA activity was generated on dissociation of the complexes, corresponding to 0.4 mol of tPA/mol of complex. SDS/PAGE of the dissociated complexes indicated a small decrease in the molecular mass of PAI-1, in agreement with proteolytic cleavage of the 'bait' peptide bond during complex-formation.

Amino Acid Sequence↗
PubMed1990

Receptors for human plasminogen on gram-negative bacteria.

A total of 188 strains representing 11 species of gram-negative bacteria were examined for the ability to interact with human plasminogen. Highly purified human plasminogen was labeled with 125I, and its uptake by different bacterial strains was measured. All 14 strains of Haemophilus influenzae and all 13 strains of Branhamella catarrhalis tested were positive with respect to plasminogen uptake. Also, eight species belonging to the family Enterobacteriaceae were tested, and of those, Proteus mirabilis demonstrated the most substantial uptake, with 28 of 39 strains taking up more than 10% of the plasminogen. Ten strains of Pseudomonas aeruginosa were also tested, of which seven showed uptake values higher than 10%. With H. influenzae and B. catarrhalis strains, Scatchard analysis indicated a two-phase receptor interaction, one more-avid receptor with a Kd of 6 to 8 nM and 2,000 to 2,500 sites per bacterium and a second receptor with a Kd of 50 to 80 nM and 9,000 sites per bacterium. With Pseudomonas aeruginosa strains, a single receptor interaction was detected with a Kd of 60 nM and the number of sites was estimated as 8,000 per bacterium. Scatchard analysis with strains of P. mirabilis indicated binding of a less-specific nature. However, plasminogen uptake by this species could be reduced by 50% by the addition of 2 mM unlabeled plasminogen. This estimate of Kd, as well as uptake studies with plasminogen fragments, suggests different properties of this receptor. With all receptor types, the addition of plasmin-aprotinin complex inhibited plasminogen uptake, which demonstrates that both forms of the molecule react with the same receptors. Plasminogen uptake could be eliminated by the addition of lysine or epsilon-aminocaproic acid, which suggests that the lysine-binding sites of the plasminogen molecule are involved in the receptor-ligand interaction.

Aprotinin↗
PubMed1989

Stability of plasminogen activator inhibitor 1 (PAI-1).

The stability of PAI-activity has been studied at different conditions. The inactivation followed first order kinetics. Lowering the temperature and decreasing the pH both, increased the stability of PAI-1 dramatically. Addition of the PAI-1 binding protein, vitronectin, to reactivated PAI-1, about doubled the half-life of PAI-1 at all conditions studied. In the presence of chloramine T, the inactivation of reactivated PAI-1 was very rapid. In this case the protective effect of purified vitronectin, human plasma or fetal calf serum, but not of bovine serum albumin, was pronounced. The stability of the spontaneously active high Mr form of PAI-1 (partially purified or in plasma), constituting a complex between PAI-1 and vitronectin, was quite similar to reactivated PAI-1 in the presence of vitronectin. Addition of pure vitronectin, human plasma or fetal calf serum to such material had no further stabilizing effect. Reactivated PAI-1, which was inactivated by incubation at physiological conditions could again be fully reactivated, in contrast to chloramine T-oxidized PAI-1, which was irreversibly inactivated.

Antigens↗