Benchmarking of abdominal surgery: a study evaluating the HARM score in a European national cohort.

BACKGROUND: Reliable, easily accessible metrics of surgical quality are currently lacking. The HARM (HospitAl length of stay, Readmission and Mortality) score is a composite measure that has been validated across diverse surgical cohorts. The aim of this study was to validate the HARM score in a national population of patients undergoing abdominal surgery. METHODS: Data on all abdominal surgery in Norwegian hospitals from 2011 to 2017 were obtained from the Norwegian Patient Registry. Readmissions and 30-day postoperative complications as well as deaths in and out of hospital were evaluated. The HARM scoring algorithm was tested after adjustment by establishing a newly proposed length of stay score. The correlation between the HARM score and complications, as well as the ability of aggregated HARM scores to discriminate between hospitals, were analysed. Risk adjustment models were developed for nationwide hospital comparisons. RESULTS: The data consisted of 407 113 primary operations on 295 999 patients in 85 hospitals. The HARM score was associated with complications and complication severity (Goodman-Kruskal γ value 0·59). Surgical specialty was the dominating variable for risk adjustment. Based on 1-year data, the risk-adjusted score classified 16 hospitals as low HARM score and 16 as high HARM score of the 53 hospitals that had at least 30 operations. CONCLUSION: The HARM score correlates with major outcomes and is associated with the presence and severity of complications. After risk adjustment, the HARM score discriminated strongly between hospitals in a European population of abdominal surgery.

ANTECEDENTES: En la actualidad no se dispone de un sistema de cuantificación numérica confiable y accesible para evaluar la calidad quirúrgica. La puntuación HARM es una medida compuesta basada en la duración de la estancia hospitalaria, los reingresos y la mortalidad postoperatoria que se ha validado en varias cohortes quirúrgicas. El objetivo de este estudio fue validar la puntuación HARM en una población nacional de pacientes sometidos a cirugía abdominal. MÉTODOS: Se obtuvieron los datos de todas las cirugías abdominales realizadas en hospitales noruegos entre 2011 y 2017 a través del registro noruego de pacientes. Se evaluaron los reingresos y las complicaciones postoperatorias a los 30 días, así como la mortalidad intra- y extra-hospitalaria. Se utilizó el algoritmo de puntuación HARM tras el ajuste con la nueva propuesta de puntuación para la duración de la estancia hospitalaria. Se analizó la correlación entre HARM y complicaciones, así como la capacidad de las puntuaciones HARM agregadas para discriminar entre hospitales. Se desarrollaron modelos de ajuste de riesgo para las comparar hospitales en todo el país. RESULTADOS: Se incluyeron 407.113 intervenciones primarias llevadas a cabo en 295.999 pacientes en 85 hospitales. La puntuación HARM se asoció con las complicaciones y la gravedad de la complicación (Goodman-Kruskal γ de 0,59). La especialidad quirúrgica fue la variable dominante para el ajuste del riesgo. Utilizando los datos de un período anual, la puntuación ajustada al riesgo clasificó a 16 hospitales como de baja puntuación y a 16 de alta puntuación de los 53 hospitales en los que se habían realizado al menos 30 intervenciones. CONCLUSIÓN: La puntuación HARM se correlaciona con los resultados principales y con la presencia y la gravedad de las complicaciones. La puntuación HARM, después del ajuste de riesgo, discrimina de forma sólida entre hospitales en una población europea de cirugía abdominal. This article is protected by copyright. All rights reserved.

Tissue factor pathway inhibitor in health and disease.

The knowledge of tissue factor pathway inhibitor (TFPI) has greatly expanded during the last few years, and TFPI is now established as a coagulation inhibitor of great importance. Its main role seems to be inhibition of small amounts of tissue factor, which probably is essential for maintaining a normal hemostatic balance. The acceleration of TFPI's inhibitory effect by heparin, the TFPI release caused by heparin injection, and TFPI's heparin affinity may greatly contribute to the anticoagulant properties of the endothelium, and may be particularly important for the outcome of vascular injury. The information provided by one single measurement of plasma TFPI in a patient is difficult to interpret, but serial measurements during the course of a disease may signal the prognosis. Recombinant TFPI has proved effective in the treatment of experimental disseminated intravascular coagulation, sepsis, and thrombosis. Whether TFPI or TFPI derivatives will be as effective in the treatment of patients remains to be determined.

Increased plasma thrombomodulin in cancer patients.

Plasma samples from 35 patients with colorectal cancer, 16 patients with pancreatic cancer and 46 patients with various cancers in the terminal stage were analysed for soluble plasma thrombomodulin with an ELISA method. At time of diagnosis and before primary treatment, the patients with colorectal cancer had normal plasma TM levels. In the patients who developed disseminated disease, the mean plasma TM level increased significantly. In the patients with pancreatic cancer, the mean plasma TM level was increased already at time of primary treatment. The TM level increased further with progress of the pancreatic cancer. In the patients with various cancer types in the terminal stage, the mean TM was also significantly increased compared to healthy controls. Great individual variation in the plasma TM level was observed, as well as great variation of mean TM level between the various cancer types. There was no significant correlation between the TM levels and the levels of tissue factor pathway inhibitor, another endothelial coagulation inhibitor, which increased with progress of malignant disease. This may indicate different underlying mechanisms for the increased plasma levels.

Effect of tissue factor pathway inhibitor (TFPI) in the HEPTEST assay and in an amidolytic anti factor Xa assay for LMW heparin.

Both the HEPTEST and amidolytic anti factor Xa assays are currently being used for heparin activity detection in plasma from patients receiving standard heparin or low molecular weight heparin (LMWH). In this study we have investigated the influence of recombinant and endogenous Tissue Factor Pathway Inhibitor (TFPI) on these assays. The HEPTEST determinations were performed on an ACL 300 R Clottimer using the APTT program which resulted in a longer incubation time with factor Xa than recommended by the manufacturer. rTFPI added to plasma prolonged the HEPTEST clotting time markedly, but had only a little effect in the amidolytic assay. Antibodies against TFPI (anti-TFPI) abolished these effects. The effect of adding rTFPI and Logiparin was additive. When anti-TFPI IgG was added to samples of normal plasma, a statistically significant shortening of the HEPTEST clotting time was seen. When anti-TFPI was added to plasma samples from volunteers who had received Logiparin by subcutaneous or intravenous injection, then the HEPTEST clotting time was shortened considerably. For some samples the clotting time was halved. These experiments show that the HEPTEST clotting time is prolonged not only by heparin-antithrombin III, but also by TFPI released by heparin injection.

The anticoagulant effect in heparinized blood and plasma resulting from interactions with extrinsic pathway inhibitor.

The influence of Extrinsic pathway inhibitor (EPI) on global clotting times of plasma was studied using activity-blocking IgG antibodies. Dilute tissue thromboplastin (TP) clotting times in plasma collected after intravenous injection of heparin were dramatically shortened by the addition of anti-EPI IgG. Anti-EPI IgG shortened the TP times to a lesser degree in plasma heparinized in vitro. Compared to plasma heparinized in vitro, the TP clotting times were markedly prolonged in post-heparin plasma of equal heparin concentration. Addition of anti-antithrombin IgG reduced the clotting times somewhat more than did anti-EPI IgG, particularly in normal plasma. In plasma from patients with cancer, about equal effect was obtained by blocking either EPI or antithrombin. These clotting time studies suggested that much of the anticoagulant effect caused by injection of heparin depended on EPI. This was confirmed by recording the release of fibrinopeptide A (FPA), as marker of thrombin generation, following addition of TP and CaCl2 to citrated blood. Thrombin generation was delayed and markedly reduced in post-heparin blood compared to that in normal blood. After incubating post-heparin citrated blood with anti-EPI IgG, the generation of FPA was more rapid; the amounts released 30 seconds after addition of TP were 6 times greater (36 vs 6 ng/ml) than in post-heparin blood without anti-EPI IgG. The subsequent FPA values were midway between pre-injection and post-heparin values. In conclusion, between one third and one half of the inhibition of TP-initiated coagulation in post-heparin plasma depends on EPI. This inhibition is mainly due to inactivation of the factor VIIa-TP complex. A small, but distinct contributing effect observed in the APTT assay (and hence no TP) indicates that even increased inactivation of activated factor X contributes. In cancer patients, these EPI-heparin interactions contribute even more to the anticoagulant effects of heparin.

Recurrent venous thrombosis during warfarin treatment related to acquired protein S deficiency.

Failure of warfarin to prevent new thrombotic processes was observed in three patients with very low free protein S concentrations and high C4b-binding protein (C4bBP) concentrations, and in one patient with hereditary protein S deficiency. We suggest that an increase in C4bBP reduces the free Protein S level, and warfarin treatment causes an additional decrease of free protein S. The four patients presented indicate that such reductions are of clinical importance. Heparin seems preferable as an anticoagulant in this situation, as warfarin given alone is ineffective, or may even be harmful. In a group of pancreatic cancer patients with advanced disease, subnormal mean free protein S was found, whereas mean total protein S concentration, and mean C4bBP concentrations were significantly higher (p less than 0.01) than in healthy controls. These findings indicate that an increase in C4bBP may induce free protein S deficiency contributing to the increased thrombotic tendency in this group of patients. The correlation between free protein S and C4bBP was 0.11, (n.s.), between total protein S and C4bBP 0.73 (p less than 0.0001).

Extrinsic pathway inhibitor (EPI) released to the blood by heparin is a more powerful coagulation inhibitor than is recombinant EPI.

EPI released to the blood after injection of heparin, as well as recombinant EPI (r-EPI) added to normal plasma prolonged both the dilute Tissue Thromboplastin (TTP) time and the Activated Partial Thromboplastin Time (APTT). It is known that EPI inhibits both factor Xa and the factor VIIa-TTP complex. The prolongation of the APTT by EPI reflects only its inhibition of factor Xa. Addition of anti-EPI immunoglobulins (IgG) to normal plasma shortened the dilute TTP time 7.3 seconds (p less than 0.001) and the APTT by 0.7 seconds (p less than 0.001). In postheparin plasma, with polybrene added to neutralize the direct effect of heparin, the TTP was about 26 seconds longer and the APTT about 9 seconds longer than baseline values. These effects were completely abolished by anti-EPI IgG, as were the effects of r-EPI. The EPI activity (chromogenic substrate-assay) of this postheparin plasma was 1.7 U/ml. The EPI activity of the plasma spiked with r-EPI to obtain comparable effects on clotting were much higher; about 22 U/ml for the TTP effect and about 5 U/ml for the APTT effect. The findings indicate that r-EPI is considerably less potent than postheparin EPI as inhibitor of plasma coagulation. This is most striking when coagulation is initiated through the extrinsic pathway. Possibly, the anticoagulant effect of r-EPI mainly depends on its Xa inhibitory effect.

The surgical treatment of gastric cancer: a retrospective study with special reference to total gastrectomy.

A retrospective study of 312 consecutive cases of gastric malignancy treated from 1974 to 1984 is presented. Eighteen patients (6%) had gastrointestinal lymphoma of the stomach. Among the remaining 294 cases with gastric carcinoma, 46 (16%) had carcinoma of the gastric stump after previous resection for peptic ulcer. Fifty-seven percent (167/294) had no distant metastases (MO). Early gastric carcinoma (pT1) occurred in 16 patients (5.8%), among whom four had distant metastases (pT1M1) and another two patients had regional lymph node metastases (pT1N1). Thirty-three percent of the patients had either no surgical treatment or an explorative laparotomy only, and 9% had a palliative bypass operation performed. A curative (48%) or palliative (10%) resection of the stomach was possible in 171/294 patients. Thus, the resectability rate was 58%. Total gastrectomy was performed in 108 cases with either curative (100) or palliative (eight) intention. The 30-day mortality was two and one patients, respectively (2.8%). Crude survival in the whole series was 16% and 11% at 5 and 10 years. After non-randomized curative total gastrectomy (100 cases) or gastric resection (40 cases) crude survival was 40% and 22% at 5 years, and 24% and 16% at 10 years, respectively (P greater than 0.05, n.s.). We found that total gastrectomy with extensive dissection and end-to-end esophago-jejunostomy by the EEA stapler can be performed with a low mortality rate (2% after curative operation) even in the upper age groups.

The present status of tissue factor pathway inhibitor.

Tissue factor pathway inhibitor (TFPI) is the factor Xa-dependent inhibitor of the factor VIIa/tissue factor complex. The plasma concentration of this 276 amino acid, 40 kDa glycoprotein is normally about 100 ng/ml. There are three intravascular pools of TFPI: 50-90% is on the endothelium, 10-50% is in plasma and less than 2.5% is in platelets. The TFPI in plasma is mainly associated with lipoproteins-only about 5% is free TFPI. The lipoprotein-associated TFPI seems to be of less anticoagulant effect than the free TFPI. Both unfractionated heparin, low-molecular-weight heparins and pentosan polysulphate induce release of TFPI after intravenous injection, whereas dermatan sulphate does not. The interactions with TFPI account for a considerable amount of the anticoagulant effect of heparin. Studies have shown increased TFPI levels in plasma from patients with advanced malignancy and in subjects with fatal DIC or septicaemia. The reason for this is unknown. For measuring the anticoagulant activity of TFPI in plasma, end-point or antigen assays may be less useful than the clotting assay with dilute tissue factor. Animal studies indicate that the main physiological role of TFPI is the inhibition of small amounts of tissue factor. TFPI is probably essential for a normal haemostatic balance.

Tissue factor pathway inhibitor with high anticoagulant activity is increased in post-heparin plasma and in plasma from cancer patients.

This study was performed in order to separate plasma fractions of tissue factor pathway inhibitor (TFPI) on the basis of TFPI's heparin binding properties. A main goal was to look for differences in anticoagulant effect of the TFPI fractions from plasma. Normal plasma and plasma with increased amounts of TFPI were used; plasma from cancer patients and post-heparin plasma (plasma drawn 5 min after heparin injection). Heparin affinity chromatography separated plasma TFPI into four fractions with increasing heparin affinity: the flow-through fraction, a low affinity fraction eluting at less than 0.3 M NaCl, an intermediate affinity fraction eluting at 0.3-0.55 M NaCl and a high affinity fraction eluting at 0.55-1.0 M NaCl. These fractions corresponded partly to the three TFPI activity fractions obtained by gel filtration. In plasma from cancer patients, the two fractions with intermediate and high heparin affinity were increased three- to four-fold, compared to normal plasma. The TFPI activity in these two fractions eluted with low-molecular-weight (35-60 kD) on gel filtration. In post-heparin plasma an even larger increase in the fraction with high heparin affinity was found; compared to that in normal plasma it was increased 14-fold. TFPI was purified to 0.72 U/mg protein in this fraction (about 43-fold compared to normal plasma TFPI). The anticoagulant effect of TFPI, relative to the chromogenic substrate TFPI activity, was greater in plasma fractions with high heparin affinity than in the other plasma TFPI fractions, and it was five-fold greater than the anticoagulant effect of recombinant TFPI. Thus, plasma TFPI is heterogenous in heparin affinity and in anticoagulant potency.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromogenic substrate assay of extrinsic pathway inhibitor (EPI): levels in the normal population and relation to cholesterol.

A two-stage chromogenic substrate assay was standardized to measure extrinsic pathway inhibitor (EPI) activity in plasma and serum samples. In the first stage, diluted plasma or serum (0-0.8%) was incubated with factor VIIa (25 pM), tissue thromboplastin (tissue factor, TF, 1% v/v) with excess binding sites for factor VIIa, and factor Xa (0.8 nM). In the second stage, excess factor X and chromogenic substrate were added as substrate for residual TF/factor VIIa catalytic activity. Heating the samples at 56 degrees C for 15 min before assay removed greater than 95% of the factor VII amidolytic activity of the samples, defibrinated the plasma, and produced only slight reduction of EPI activity. The coefficient of variation for the same sample assayed on different days was 8.7-10.6% and the intra-assay coefficient of variation was 5.0%. Addition of anti-EPI immunoglobulin to normal plasma completely abolished the EPI activity of the sample. EPI activity was stable in plasma samples stored at -20 degrees C, but in serum, some samples lost greater than 50% activity after 3 months at -70 degrees C. Median EPI activity of umbilical cord blood was 45% (range 33-93%). In a cohort of healthy blood donors (n = 176) EPI activity was significantly correlated with age; the regression line was y = 68% + 0.60x (r = 0.39). The approximated standard deviation for the regression line was 17.9% and the age-adjusted reference limits were determined. Equal levels were seen in males and females.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue factor pathway inhibitor prevents thrombus formation on procoagulant subendothelial matrix.

The effect of recombinant tissue factor pathway inhibitor (rTFPI) on extracellular matrix procoagulant activity was studied in a human ex vivo model of thrombogenesis. Extracellular matrix of endotoxin stimulated endothelial cells perfused with human non-anticoagulated blood at a wall shear rate of 100/s induced pronounced fibrin deposition, which covered 82 +/- 11% of the matrix surface within 5 min. Preincubating the matrix with the combination of rTFPI, factor VIIa (FVIIa) and factor Xa (FXa) reduced fibrin deposition to levels observed with matrix from non-stimulated endothelial cells (7 +/- 6% fibrin coverage, P < 0.001). Preincubation with rTFPI plus FXa also reduced fibrin deposition significantly, but to a lesser extent (41 +/- 6% fibrin coverage, P < 0.001). Preincubation with rTFPI alone, or with rTFPI plus FVIIa, did not affect fibrin deposition. The inhibition of thrombus formation on procoagulant extracellular matrix by rTFPI seemed to be FXa-dependent, and a result of TFPI's ability to bind and inhibit both TF activity as well as FXa. The results from this study suggest a future role for rTFPI as an agent for prevention of TF-induced vascular thrombosis.