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We present a restriction fragment length polymorphism (RFLP) analysis of 29 benign and 30 malignant prostatic tumors, using polymorphic DNA probes to the putative tumor suppressor genes DCC (Deleted in Colorectal Carcinoma; chromosome 18q21.3), nm23-H1 (17q21.3), APC (Adenomatous Polyposis Coli; 5q21) and p53 (17p13). Six of 23 evaluable cancers (26%) showed loss of heterozygosity (LOH) at DCC; 5 were advanced stage and one was clinically localized (p < 0.05). Mapping 18q deletions, another (advanced) cancer showed LOH at a locus distal to DCC (18q22), but no LOH at DCC. Three of 15 evaluable cancers (20%), all advanced, showed LOH at APC. Three of eight (38%) cancers, of which 2 were advanced, showed LOH at p53. One high grade/stage cancer of 21 (5%) showed LOH at nm23-H1 (and also at DCC). Combining data, allelic losses at either DCC, APC, or p53 genes were seen in 13% of localized cancers, but in 71% of advanced cancers (p < 0.002). Allelic loss involving nm23-H1 is rare in prostatic carcinoma. We suggest that loss of tumor suppressor genes DCC and/or an unidentified gene located distally on chromosome 18q, APC, or p53 may influence progression in prostatic carcinoma.

1. The effects and binding characteristics of a series of chimeric galanin-neuropeptide Y (NPY) peptides were examined in various preparations known to contain a predominant population of either Y1 or Y2 receptors for NPY or galanin receptors. 2. NPY suppressed the electrically stimulated twitches of the rat vas deferens (Y2 receptors), while galanin enhanced the electrically stimulated twitches. The galanin-NPY peptides M 32 (galanin(1-13)-NPY(25-36)), M69A (galanin(1-13)-Lys-[epsilon NH-Gly-NPY(4-1)]NPY(25-36)) and M88 (galanin(1-12)-Ala-NPY(25-36)) evoked a concentration-dependent suppression of the electrically stimulated twitches. These chimeric peptides were about equipotent with NPY, while NPY (13-36) was about five times less potent than NPY itself. Also a stochiometric combination of the N- and C-terminal fragments NPY (1-24)NH2 and NPY (25-36) (each at 1 microM) was inactive in vas deferens. M120 (galanin (1-13)-NPY(14-36) (1 microM) did not affect the NPY-mediated suppression of the stimulated twitches. 3. NPY evoked a concentration-dependent contraction in the guinea-pig isolated caval vein (Y1 receptors), while galanin (< or = 1 microM) was inactive. M32, M69A and M88 induced a slight contraction at very high concentrations only (> or = 0.3 M), while M120 was inactive at 1 microM. None of the four chimeric peptides affected the contraction evoked by NPY. 4. Since the number of NPY receptors in the rat vas deferens and guinea-pig caval vein were too low,the affinities of the galanin-NPY peptides for [3H]-NPY binding sites were examined in membranes from rat brain areas known to contain predominant populations of Y1 receptors (cerebral cortex) and Y2 receptors (hippocampus), respectively. The chimeric peptides M32, M69A, M88, M120 and NPY (13-36)all had higher affinities for hippocampal binding sites than for cerebral cortical binding sites. These peptides were 90-440 times less potent than NPY at cerebral cortical binding sites and 15-125 times less potent than NPY at hippocampal binding sites. The most selective chimeric peptide was M32, which had a 20 fold higher affinity for hippocampal than for cerebral cortical binding sites.5. At hypothalamic [125I]-galanin binding sites M32, M88 and M69A were equipotent with galanin,while M120 was about 10 times less potent than galanin. M32, M88 and M69A, like galanin contracted the rat isolated jejunum.6. The N-terminal portion (1-12) of galanin seems to permit a steric conformation of the attached NPY (25-36) part of the chimeric galanin-NPY peptides, which results in a facilitated Y2 but not Y1.receptor recognition and activation. None of the galanin-NPY peptides appeared to act as antagonists at either type of NPY receptor, probably due to their low affinity. Instead, they displayed a very high affinity for hypothalamic galanin receptors and probably act as galanin agonists in the rat jejunum.

Genomic clones encompassing the Huntington disease (HD) mutation were used to isolate a probe that detects size changes in the restriction fragments that contain the HD trinucleotide repeat (TNR). This probe also detects a frequent Sau3A polymorphism (allele sizes 1.8-kb and 2.7kb), which maps approximately 950bp from the TNR. Examination of a number of HD families established that the frequency of the Sau3A alleles did not differ significantly between control and HD populations; however, the HD expansion was always present on a chromosome that contained the 1.8-kb Sau3A allele. This association between a specific allele and the HD TNR expansion was significant and could provide a clue to the chromosomal elements that produce the trinucleotide expansion on the Huntington disease chromosome.

We conducted a cross-sectional study of antithrombin III (ATIII), protein C (PC) and plasminogen (Plg) concentrations in a population of healthy plasma donors in the Trent Region. The distribution of values for protein C was log normal whereas for ATIII and Plg the distributions were positively skewed and differed significantly from normal and log normal. Males had higher antithrombin III concentrations (mean 1.10 iu/ml, range 0.72-1.65) than females (mean 1.07 iu/ml, range 0.75-1.69) (P = 0.001) and levels increased with age in women. Younger women aged 25-34 had significantly lower plasma concentrations of ATIII compared to males of similar age. For protein C, concentrations were higher in males (mean 1.07 u/ml, range 0.37-2.11) than in females (mean 1.01 u/ml, range 0.59-1.61) (P < 0.001) and levels increased with age in both sexes P < 0.001). In women, a novel difference in protein C concentration between ABO blood groups was noted. There was no significant difference in plasminogen concentration between males and females, and in women plasminogen decreased with age (r = -0.205, P < 0.001). We conclude that these variations in ATIII and protein C with age and sex are important considerations in the determination of reference ranges for these proteins.

The serine proteinase inhibitor antithrombin III (ATIII) is a key regulatory protein of intrinsic blood coagulation. ATIII attains its full biological activity only upon binding polysulfated oligosaccharides, such as heparin. A series of synthetic peptides have been prepared based on the proposed heparin binding regions of ATIII and their ability to bind heparin has been assessed by CD spectrometry, by isothermal titration calorimetry, and by the ability of the peptides to compete with ATIII for binding heparin in a factor Xa procoagulant enzyme assay. Peptide F123-G148, which encompasses both the purported high-affinity pentasaccharide binding region and an adjacent, C-terminally directed segment of ATIII, was found to bind heparin with good affinity, but amino-terminal truncations of this sequence, including L130-G148 and K136-G148 displayed attenuated heparin binding activities. In fact, K136-G148 appears to encompass only a low-affinity heparin binding site. In contrast, peptides based solely on the high-affinity binding site (K121-A134) displayed much higher affinities for heparin. By CD spectrometry, these high-affinity peptides are chiefly random coil in nature, but low microM concentrations of heparin induce significant alpha-helix conformation. K121-A134 also effectively competes with ATIII for binding heparin. Thus, through the use of synthetic peptides that encompass part, if not all, of the heparin binding site(s) within ATIII, we have further elucidated the structure-function relations of heparin-ATIII interactions.

A multiple sequence alignment among aspartate aminotransferase, dialkylglycine decarboxylase, and serine hydroxymethyltransferase (DAS) was used for profile databank search. The DAS profile could detect similarities to other pyridoxal or pyridoxamine phosphate-dependent enzymes, like several gene products involved in dideoxysugar and deoxyaminosugar synthesis. The alignment among DAS and such gene products shows the conservation of aspartate 222 and lysine 258, which, in aspartate aminotransferase, interacts with the N1 of the coenzyme pyridine ring and forms the internal Schiff base, respectively. The lysine is replaced by histidine in the pyridoxamine phosphate-dependent gene products. The alignment indicates also that the region encompassing the coenzyme binding site is the most conserved.

The effects of oral and transdermal administration of estrogen replacement therapy (ERT) have been fairly well investigated regarding lipoprotein and carbohydrate metabolism, while the effects of different modes of estrogen administration on the haemostatic system have been less well studied. To delineate and compare the effects of perorally administered conjugated estrogens (CE) and transdermally administered estradiol (E2) in doses needed for hormone replacement therapy (HRT) on haemostasis parameters, 23 postmenopausal women were engaged in a study with an open cross-over design. The doses compared (0.625 mg CE and 50 micrograms E2/24h) are the lowest which, with few exceptions, eliminate climacteric symptoms. Both CE and E2 increased factor VII:C, factor VII:Ag, and the prothrombin fragment1 + 2. The increase in factor VII:Ag, however, was significantly higher after treatment with CE. These changes were all towards a state of hypercoagulability. Furthermore, CE decreased plasminogen activator inhibitor (PAI) and the thrombin-antithrombin complexes (TAT), as well as antithrombin (ATIII).

We reported that recombinant human soluble thrombomodulin (rhs-TM) is effective for disseminated intravascular coagulation (DIC) in vivo, in mice and rats. In the present work, we investigated the effects of decreased plasma antithrombin III (ATIII) levels on anticoagulant effects of rhs-TM, as compared to findings with heparin, of which effect is lowered by the decreased plasma ATIII levels in patients with DIC. Rat plasma ATIII levels decreased when we mixed plasma with anti-rat ATIII antibody and the potential of heparin to prolong APTT or PT was markedly diminished. The potential of rhs-TM to prolong APTT and PT was not affected. In rats injected with anti-rat ATIII antibody, plasma ATIII levels decreased immediately. When the rats were infused with tissue factor (TF), DIC was induced. At doses of rhs-TM and heparin which were equally effective at inhibiting the decrease in platelet count and fibrinogen level in control rats treated with TF, only rhs-TM remained effective in preventing DIC in rats with reduced ATIII levels. Heparin was not effective when administered to these rats with reduced ATIII levels. Therefore, rhs-TM effectively inhibits coagulation independent of ATIII levels, in contrast to heparin, which depends on the ATIII level.

A new, sensitive and specific immunocapture enzyme (ICE) assay for quantitation of the enzymatic activity of cancer procoagulant (CP) has been developed. The assay had good reproducibility (inter- and intra-assay CV were 6.4% and 5.7% respectively) and was linear for concentrations of CP from 0.5 microgram/ml to 10 micrograms/ml (r2 = 0.995). Using this assay the inhibition of CP by iodoacetamide, mercuric chloride, E-64, leupeptin and antipain was demonstrated. There was no significant effect of cystatin and natural plasma proteinase inhibitors alpha 1-antitrypsin, alpha 1-antichymotrypsin, alpha 2-macroglobulin and antithrombin-III/heparin, on the activity of the CP.

The analysis of the androgen receptor (AR) gene, mRNA, and protein in a subject with X-linked Reifenstein syndrome (partial androgen insensitivity) is reported. The presence of two mature AR transcripts in genital skin fibroblasts of the patient is established, and, by reverse transcriptase-PCR and RNase transcription analysis, the wild-type transcript and a transcript in which exon 3 sequences are absent without disruption of the translational reading frame are identified. Sequencing and hybridization analysis show a deletion of > 6 kb in intron 2 of the human AR gene, starting 18 bp upstream of exon 3. The deletion includes the putative branch-point sequence (BPS) but not the acceptor splice site on the intron 2/exon 3 boundary. The deletion of the putative intron 2 BPS results in 90% inhibition of wild-type splicing. The mutant transcript encodes an AR protein lacking the second zinc finger of the DNA-binding domain. Western/immunoblotting analysis is used to show that the mutant AR protein is expressed in genital skin fibroblasts of the patient. The residual 10% wild-type transcript can be the result of the use of a cryptic BPS located 63 bp upstream of the intron 2/exon 3 boundary of the mutant AR gene. The mutated AR protein has no transcription-activating potential and does not influence the transactivating properties of the wild-type AR, as tested in cotransfection studies. It is concluded that the partial androgen-insensitivity syndrome of this patient is the consequence of the limited amount of wild-type AR protein expressed in androgen target cells, resulting from the deletion of the intron 2 putative BPS.

The pathogenesis of scrapie, a transmissible subacute spongiform encephalopathy, is unclear. However, certain aspects of the known cellular and molecular neuropathology in scrapie led us to hypothesize that cytokines could mediate cerebral pathological changes in this neurodegenerative disease. Therefore, expression of multiple cytokine genes in the brain and peripheral organs of scrapie-infected mice was examined. Late in the course of scrapie, expression of tumor necrosis factor alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and IL-1 beta mRNA was markedly increased in the brain but not the spleen, kidneys, or liver. In time course studies, scrapie-infected mice exhibited increased cerebral expression of the TNF-alpha, IL-1 alpha, and IL-1 beta mRNAs by week 15 postinoculation--a time point that coincided with the onset of clinical symptoms. Thereafter, the levels of these cytokine transcripts increased progressively to the terminal stages of of the disease (week 25). To determine the relationship of the increased cerebral expression of the cytokine mRNAs to the development of pathological changes in scrapie, we examined the expression of the glial fibrillary acidic protein gene (a marker for astrocytosis) and the murine acute-phase response gene homologous to the alpha 1-antichymotrypsin gene (designated EB22/5.3). Markedly increased expression of both the glial fibrillary acidic protein and EB22/5.3 mRNAs was observed in the brain but not the peripheral organs of scrapie-infected mice. The increased expression of both these gene products also occurred at week 15 of infection and, thereafter, increased progressively to the terminal stages of the disease. Therefore, infection of mice with scrapie resulted in significant increases in the expression of the TNF-alpha, IL-1 alpha, and IL-1 beta gene products, whose pattern correlated with the onset and development of molecular and clinical pathological changes. Since scrapie is known not to evoke an immune response, the present findings strongly suggest the existence of a localized cerebral host response to the agent during which proinflammatory cytokines could be key pathogenic mediators.

A prospective randomised multicentre clinical study was undertaken for 2 years and 3 months from November 1982, with the aim of examining the significance of using a combination of ftorafur (FT) and tamoxifen (TAM) for post-operative adjuvant therapy of breast cancer. Patients had either stage II or stage IIIa disease, were age 75 or below and had undergone radical mastectomy. Patients were divided into two groups and received one of the following treatment protocols: treatment A, intravenous administration of doxorubicin (DOX), 20 mg on the day of surgery and 10 mg the next day, followed by oral FT 50 mg day-1 for 2 years from the 14th day; treatment B, the same pattern of DOX administration for the first 2 days, followed by a combined therapy of FT and TAM 20 mg day-1 for 2 years. The number of patients was 546 (treatment A 274 and treatment B 272), of whom 34 (6%) were ineligible. The remaining 512 patients (treatment A 254 and treatment B 258) were followed up for 5 years for analysis. Significantly higher 5 year disease-free rate and 5 year survival rates were observed with treatment B compared with treatment A. When seen in terms of background factors, node-positive patients appeared to derive more benefit from tamoxifen than node-negative patients, but the oestrogen receptor-negative and premenopausal subgroups appeared to derive about the same benefit as those who were oestrogen receptor positive and post-menopausal. Indeed, survival in the premenopausal group was significantly better with tamoxifen (P = 0.04). No increase in side-effects was seen by combining TAM with FT. The study results demonstrate that concomitant administration of FT and TAM is better than FT alone for post-operative adjuvant therapy for breast cancer.

dcd (dCTP deaminase) mutants of Escherichia coli were reported not to require thymidine for growth even though most of the thymidylate that is synthesized de novo arises from cytosine nucleotides through a pathway involving dCTP deaminase. We found, however, that the fresh introduction of dcd mutations into many strains of E. coli produced a requirement for thymidine for optimum aerobic growth, but the mutants readily reverted to prototrophy via mutations in other genes. One such mutation was in deoA, the gene for deoxyuridine phosphorylase. However, a dcd deo mutant became thymidine dependent once again if a cdd mutation (affecting deoxycytidine deaminase) were introduced. The results indicate that dcd mutants utilize an alternative pathway of TMP synthesis in which deoxycytidine and deoxyuridine are intermediates. A cdd mutation blocks the pathway by preventing the conversion of deoxycytidine to deoxyuridine, whereas a deoA mutation enhances it by sparing deoxyuridine from catabolism. The deoxycytidine must arise from dCTP or dCDP via unknown steps. It is not known to what extent this pathway is utilized in wild-type cells, which, unlike the dcd mutants, do not accumulate dCTP.

The pathways of pectin and galacturonate catabolism in Erwinia chrysanthemi converge to form a common intermediate, 2-keto-3-deoxygluconate (KDG), which is phosphorylated by KDG kinase encoded by the kdgK gene. We cloned the kdgK gene of E. chrysanthemi 3937 by complementing an Escherichia coli kdgK mutation, using an RP4-derivative plasmid. One of the kdgK R-prime plasmids harbored a DNA insert of about 80 kb and carried the uxuA and uxuB genes involved in glucuronate catabolism and the celY gene coding for an E. chrysanthemi cellulase. The kdgK and celY genes were precisely located on this plasmid, and their respective transcriptional directions were determined. The nucleotide sequence of the kdgK region indicated that the kdgK reading frame is 981 bases long, corresponding to a protein of 329 amino acids with a molecular mass of 36,377 Da. Analysis of the deduced primary amino acid sequence showed that this enzyme is a new member of the PfkB family of carbohydrate kinases. Expression of kdgK is controlled by a negative regulatory gene, kdgR, which represses all the steps of pectin degradation. Near the putative promoter of the kdgK gene, we identified a putative KdgR-binding site and demonstrated that the KdgR protein specifically binds in vitro to this DNA region. The KdgR-KDG couple directly mediates the phenomenon of repression or induction. The KDG kinase, by limiting the intracellular inducer concentration, appears to be a key enzyme in induction of the whole catabolic pathway.

Previous studies have shown that tissue-factor-pathway inhibitor (TFPI) is an important regulator of the extrinsic pathway of blood coagulation through its ability to inhibit factor Xa and factor VIIa-tissue factor activity. We describe the molecular cloning and expression of a full-length cDNA that encodes a molecule, designated TFPI-2, that has a similar overall domain organization and considerable primary amino acid sequence homology to TFPI. After a 22-residue signal peptide, the mature protein contains 213 amino acids with 18 cysteines and two canonical N-linked glycosylation sites. The deduced sequence of mature TFPI-2 revealed a short acidic amino-terminal region, three tandem Kunitz-type domains, and a carboxyl-terminal tail highly enriched in basic amino acids. Northern analysis indicates that TFPI-2 is transcribed in umbilical vein endothelial cells, liver, and placenta. TFPI-2 was expressed in baby hamster kidney cells and purified from the serum-free conditioned medium by a combination of heparin-agarose chromatography, Mono Q FPLC, Mono S FPLC, and Superose 12 FPLC. Purified TFPI-2 migrated as a single band in SDS/PAGE and exhibited a molecular mass of 32 kDa in the presence and absence of reducing agent. The amino-terminal sequence of recombinant TFPI-2 was identical to that predicted from the cDNA. Despite its structural similarity to TFPI, the purified recombinant TFPI-2 failed to react with polyclonal anti-TFPI IgG. Preliminary studies indicated that purified recombinant TFPI-2 strongly inhibited the amidolytic activities of trypsin and the factor VIIa-tissue factor complex. In addition, the inhibition of factor VIIa-tissue factor amidolytic activity by recombinant TFPI-2 was markedly enhanced in the presence of heparin. TFPI-2 at high concentrations weakly inhibited the amidolytic activity of human factor Xa, but had no measurable effect on the amidolytic activity of human thrombin.

In the treatment of cardiovascular disease, it could be of therapeutic interest to associate the hypotensive effects due to the inhibition of angiotensin II formation with the diuretic and natriuretic responses induced by the protection of the endogenous atrial natriuretic peptide (ANP). Investigation of this hypothesis requires an orally active compound able to simultaneously inhibit angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), which is involved in renal ANP metabolism. Such compounds have been rationally designed by taking into account the structural characteristics of the active site of both peptidases. Among them, RB 105, N-[(2S,3R)-2-mercaptomethyl-1-oxo-3-phenylbutyl]-(S)-alanine, inhibited NEP and ACE with Ki values of 1.7 +/- 0.3 nM and 4.2 +/- 0.5 nM, respectively. Intravenous infusion of RB 105 in conscious spontaneously hypertensive rats prevented the pressor response to exogenous angiotensin I and potentiated the natriuretic response to ANP. Infusion of RB 105, at 2.5, 5, 10, 25, and 50 mg/kg per hr decreased blood pressure dose-dependently in conscious catheterized spontaneously hypertensive rats and increased diuresis and natriuresis. Infusion of RB 105 as a bolus of 25 mg/kg followed by 25 mg/kg per hr similarly decreased blood pressure and increased natriuresis in three different models of hypertension (renovascular, deoxycorticosterone acetate-salt, and spontaneously hypertensive rats). Mixanpril, a lipophilic prodrug of RB 105 (ED50 values when given orally to mice, 0.7 mg/kg for NEP; 7 mg/kg for ACE), elicited dose-dependent hypotensive effects of long duration in spontaneously hypertensive rats after oral administration [-37 mmHg for 50 mg/kg twice a day (1 mmHg = 133 Pa) and is therefore the first dual NEP/ACE inhibitor potentially useful for clinical investigations.

The present investigation evaluated the serum transferrin receptor concentration in subjects with nontransfusional iron overload who were identified in two separate studies on the basis of a serum ferritin level above 400 micrograms/L. Subjects with preclinical hereditary hemochromatosis were evaluated in the first study and those with the African form of iron overload in the second. In the first study, hereditary hemochromatosis was identified in 14 white men on the basis of a persistent elevation in transferrin saturation above 55%. The serum receptor concentration was elevated above the upper cut-off of 8.5 mg/L in two of the subjects, but the mean receptor of 6.1 +/- 1.4 mg/L (mean +/- 2 SE) did not differ significantly from the normal mean for this assay of 5.6 +/- 0.3 mg/L. In the same study, 60 control subjects with secondary iron overload were identified on the basis of a serum ferritin persistently above 400 micrograms/L, with a normal serum C-reactive protein concentration but with a transferrin saturation < 55%. Three of these subjects had an elevated serum receptor concentration but the mean value of 5.5 +/- 0.4 mg/L did not differ from normals nor from subjects with hemochromatosis. In the second study, 49 black Africans with iron overload were divided into those with or without an elevated transferrin saturation. The mean serum receptor concentration of 5.0 +/- 0.8 mg/L and 4.5 +/- 0.4 mg/L, respectively, did not differ statistically. It was concluded that there is no evidence of generalized dysregulation of the transferrin receptor in hemochromatosis or African siderosis.

The antiestrogen tamoxifen (TAM) is an effective therapy for advanced breast cancer. However, its use is limited by the eventual development of acquired TAM resistance in many patients. There is now strong evidence to suggest that prolactin plays an important role in advanced breast cancer. We have measured plasma prolactin (PRL) and estrogen-receptor (ER) and progesterone-receptor (PR) in post-menopausal patients with breast cancer (Stage III, n = 44). The blood samples were collected pre-operatively and sequentially thereafter for a minimum period of 3 years or until the death of the patients. The ER and PR were estimated in breast tumor samples by dextran-coated charcoal (DCC) method. The patients were treated with surgery and radiotherapy followed by TAM (10 mg, 1 BD). Based on the response to treatments, the patients were divided into two groups: (1) TAM sensitive (n = 19) and (2) TAM resistant (n = 25). In the TAM sensitive group, patients responded to the treatment and did not develop progressive disease within a period of 3 years. On the contrary, in the group of TAM resistant, patients developed progressive disease within a period of 3 years. The development of progressive disease clearly indicated TAM resistance. Plasma PRL correlated well with the disease progression. This study clearly demonstrated that plasma prolactin accurately indicated the response and development of resistance to TAM in patients with advanced breast cancer.

Antithrombin-III (AT) is a key inhibitor of blood coagulation that neutralizes activated serine esterases by forming covalent modified complexes (ATm). A new monoclonal antibody directed against short-lived AT-activated serine protease complexes provides a means of measuring subclinical coagulation activity during cardiopulmonary bypass (CPB). Twelve patients undergoing CPB for coronary artery bypass grafting were studied and AT, ATm, D-dimers (DD), and several other coagulation and fibrinolytic markers were measured during the surgical procedure. There were decreases in AT, factors V, II, X, IX, protein S (total and free), C4b-binding protein, thrombomodulin, and platelets counts, whereas heparin, ACT, thrombospondin, plasminogen activator inhibitor (PAI-1), and tissue plasminogen activator (tPA) increased. ATm and the percentage of ATm available (ATm/AT) showed a peak during CPB. These results demonstrate that during CPB, the use of heparin produces an equilibrium involving increased coagulation activation and consumption in association with increased fibrinolysis. The equilibrated consumption of both coagulation and fibrinolytic factors leads to low levels of all factors after cardiac surgery. The ATm assay allows assessment of the differential effects of CPB and surgical trauma on coagulation activation. It is speculated that ATm levels may be useful in monitoring the consumption of coagulation factors.