Weight Loss Reduces Tissue Factor in Morbidly ... - Wiley Online Library

Weight Loss Reduces Tissue Factor in Morbidly Obese Patients Christoph W. Kopp,* Hans-Peter Kopp,† Sabine Steiner,* Stephan Kriwanek,‡ Katarzyna Krzyzanowska,† Andrea Bartok,* Rudolf Roka,‡ Erich Minar,* and Guntram Schernthaner†

Abstract KOPP, CHRISTOPH W., HANS-PETER KOPP, SABINE STEINER, STEPHAN KRIWANEK, KATARZYNA KRZYZANOWSKA, ANDREA BARTOK, RUDOLF ROKA, ERICH MINAR, AND GUNTRAM SCHERNTHANER. Weight loss reduces tissue factor in morbidly obese patients. Obes Res. 2003;11:950 –956. Objective: To investigate the tissue factor (TF) pathway in clinical obesity and associated metabolic syndrome. Research Methods and Procedures: Thirty-seven morbidly obese patients (4 men; BMI, 48 ⫾ 7 kg/m2; range, 42 to 53 kg/m2), undergoing elective gastroplasty for the induction of weight loss, were examined for hemostatic, metabolic, and inflammatory parameters at baseline and 14 ⫾ 5 months postoperatively. Results: Weight loss significantly reduced circulating plasma TF (314 ⫾ 181 vs. 235 ⫾ 113 pg/mL, p ⫽ 0.04), coagulation factor VII (130 ⫾ 22% vs. 113 ⫾ 19%, p ⫽ 0.023), and prothrombin fragment F1.2 (2.4 ⫾ 3.4 vs. 1.14 ⫾ 1.1 nM, p ⫽ 0.04) and normalized glucose metabolism in 50% of obese patients preoperatively classified as diabetic or of impaired glucose tolerance. The postoperative decrease in plasma TF correlated with the decrease of F1.2 (r ⫽ 0.56; p ⫽ 0.005), a marker of in vivo thrombin formation. In subgroup analysis stratified by preoperative glucose tolerance, baseline circulating TF (402.6 ⫾ 141.6 vs. 176.2 ⫾ 58.2, p ⬍ 0.001) and TF decrease after gastroplasty (⌬TF: 164.7 ⫾ 51.4 vs. ⫺81 ⫾ 31 pg/mL, p ⫽ 0.02) were significantly higher in obese patients with impaired

Received for review December 9, 2002. Accepted in final form June 11, 2003. *2nd Department of Medicine, Angiology Division, University of Vienna, Vienna, Austria; †1st Department of Medicine, Rudolfstiftung Hospital, Vienna, Austria; and ‡1st Department of Surgery & Ludwig Boltzmann Institute for Endocrine Surgery, Rudolfstiftung Hospital, Vienna, Austria Address correspondence to Christoph W. Kopp, 2nd Department of Medicine, Division of Angiology, University of Vienna, General Hospital (AKH), Waehringer Guertel 18-20, A-1090 Wien, Austria. E-mail: [email protected] Copyright © 2003 NAASO

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glucose tolerance than in patients with normal glucose tolerance. Discussion: Procoagulant TF is significantly reduced with weight loss and may contribute to a reduction in cardiovascular risk associated with obesity. Key words: morbid obesity, impaired glucose tolerance, diabetes, gastroplasty, coagulation

Introduction

Tissue factor (TF),1 the main trigger of coagulation in vivo, has been recognized as a key player in atherothrombosis, and elevated circulating TF has been associated with increased cardiovascular risk (1). Recently, expression of TF has been demonstrated as significantly induced in adipose tissue of leptin-deficient (ob/ob) obese mice and has been associated with increased mRNA levels of transforming growth factor-beta (TGF␤) (2,3). In obese patients, altered expression of proteins participating in the fibrinolytic and the coagulation cascade may contribute to the increased cardiovascular risk associated with this condition. In this respect, a hypofibrinolytic state resulting from an increased plasma level of plasminogen activator inhibitor-1 (4) and elevated plasma levels of coagulation factor VII and fibrinogen was reported in obese patients (5,6). However, the role of circulating TF in morbidly obese patients has not been studied. Obesity with a BMI ⬎35 kg/m2 has been shown to increase the risk of developing type 2 diabetes by more than 60-fold in women and by 42-fold in men (7). Elevated TF antigen has been reported in patients with microvascular complications of diabetes and premature atherosclerosis, predisposing them to increased cardiovascular risk (8 –10). Importantly, several studies focusing on surrogate markers of atherosclerosis have shown improvement of the athero-

1 Nonstandard abbreviations: TF, tissue factor; TFPI, tissue factor pathway inhibitor; TGF␤-1, transforming growth factor-beta1; IL, interleukin; CRP, C-reactive protein; hsCRP, high sensitive C-reactive protein; HbA1c, hemoglobin A1c.

Weight Loss and Tissue Factor, Kopp et al.

genic profile associated with weight loss, a profile resulting from the decrease of proinflammatory and antifibrinolytic parameters (11). A large population-based observational study of overweight individuals with diabetes demonstrated a substantial reduction in total and cardiovascular disease and diabetes mortality after intentional weight loss (12). Proinflammatory and procoagulant pathways are closely linked, and aberrant expression of TF has been suggested to promote thrombotic episodes, e.g., in gram-negative sepsis, systemic lupus erythematosus, Crohn’s disease, rheumatoid arthritis, and various forms of cancer (13,14). Tissue factor pathway inhibitor (TFPI), the natural antagonist of TF, is mainly produced by endothelial cells (15) and inhibits TF/VIIa in a factor Xa-dependent manner (16). The anticoagulantly active, free form of TFPI has been associated with parameters of the insulin resistance syndrome (17) and BMI (18). TFPI activity was described as elevated in elderly patients with impaired glucose tolerance and type 2 diabetes (19). In this prospective, longitudinal study in morbidly obese patients, we investigated the relation between the TF pathway and obesity, the obesity-associated metabolic syndrome, and the effect of weight loss. As numerous studies have shown a strong and independently predictive role of inflammatory markers for cardiovascular risk (20,21), we further investigated the systemic antigen level of adipocytederived proinflammatory cytokines, hormones, and growth factors such as interleukin-6 (IL-6), leptin, and TGF␤-1 and their potential role in the induction of TF in obesity (22–24).

Research Methods and Procedures Subjects Thirty-seven morbidly obese patients (four men) undergoing gastroplasty for induction of weight loss were included in the study. Indication for surgery was based on the guidelines of the National Institute of Health consensus statement for surgery in severe obesity with BMI of ⬎40 kg/m2 or BMI ⬎35 kg/m2 in patients with obesity-related concomitant disease (25). Exclusion criteria were symptomatic cardiovascular disease, infectious disease, overt eating disorders, heavy alcohol consumption, major psychiatric disease, hepatic or renal failure, Cushing syndrome, thyroid dysfunction, or other major endocrine disorders. The study was performed in accordance with the Declaration of Helsinki, and written informed consent was obtained from all study participants. Study Design and Surgical Procedure In a prospective longitudinal study, metabolic, hemostatic, and inflammatory parameters were measured before and 14 ⫾ 5 months after vertical gastroplasty performed as described by Mason et al. (26).

Laboratory Measurements Blood samples for the measurement of circulating TF (plasma), total and free TFPI (plasma), factor VII (plasma), F1.2 (plasma), TGF␤-1 (plasma), IL-6 (serum), and high sensitive C-reactive protein (CRP; plasma) were collected after overnight fasting for at least 8 hours; the oral glucose tolerance test was performed in the same session. Plasma was prepared from anticoagulated blood by centrifugation for 10 minutes at 3000 rpm and 4 °C; samples were frozen immediately at ⫺80 °C until analysis. A standard oral glucose tolerance test was performed with 75 g glucose to detect impaired glucose tolerance or type 2 diabetes; the glucose tolerance status was defined in accordance with the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (27). The diagnostic criteria for diabetes were a fasting plasma glucose of ⬎125 mg/dL or a 2-hour value of ⬎199 mg/dL. Blood pressure was measured using a mercury sphygmomanometer under resting conditions. Blood glucose, cholesterol, high-density lipoprotein-cholesterol, and triglycerides were measured by enzymatic in vitro tests (Roche Diagnostics Corp., Indianapolis, IN). Insulin concentration was quantitated by immunoassay (Enzymuntest Insulin, ES 600; Boehringer Mannheim, Mannheim, Germany). Intra- and interassay coefficients of variation were 3.5% and 5.6%, respectively. The immunoassays used to determine plasma TF (Imubind Tissue Factor ELISA, No. 845) and total and free TFPI (Imubind truncated TFPI, No. 850) were purchased from American Diagnostica (Greenwich, CT) and performed according to the manufacturer’s instructions. Coagulation factor VII-antigen ELISA was purchased from Asserachrom (Diagnostica Stago, Asnieres-sur-Seine, France), and prothrombin fragment F1.2 ELISA (Enzygnost F1.2 micro) was from Dade Behring, Germany. Quantikine ELISA to determine human TGF␤-1 (DB100), IL-6, and leptin (DLP00) was from R&D Systems (Wiesbaden, Germany). High sensitive CRP (hsCRP) was measured by ELISA (Aurica DRG International, Marburg, Germany). Intra- and interassay coefficients of variation were 5.1% and 14.3% for CRP, 3.2% and 5.4% for TGF␤-1, 3.8% and 9.9% for IL-6, and 3.7% and 7.1% for leptin, respectively. Determination of fibrinogen was performed on a STA coagulation analyzer according to the manufacturer’s recommendation (Diagnostica Stago). Statistical Analysis Epidemiological and metabolic data are given as mean ⫾ SD. Pre- and postoperative data were compared by paired Student’s t test, and correlations were calculated according to Pearson. Correction for multiple testing was performed according to Bonferroni Holm. Differences in the frequency of the glucose tolerance before and after surgery were OBESITY RESEARCH Vol. 11 No. 8 August 2003

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Table 1A. Patient characteristics and metabolic parameters before and after gastroplasty Interval: 14 ⴞ 5 months Age (years) Sex (female/male) Height (cm) Weight (kg) BMI (kg/m2) Blood pressure (mm Hg) Systolic Diastolic Glucose (mM) Fasting 1-hour 2-hour Insulin (␮U/mL) Fasting 1-hour 2-hour C-peptide (nM) HbA1c (%) Triglyceride (mM) Cholesterol (mM) High-density lipoprotein-cholesterol (mM) Low-density lipoprotein-cholesterol (mM)

Preoperative (n ⴝ 37)

Postoperative (n ⴝ 37)

p Value

41 ⫾ 7 33/4 167 ⫾ 5 136 ⫾ 23 49 ⫾ 7

92 ⫾ 17 33 ⫾ 6

0.0001 0.0001

148 ⫾ 20 91 ⫾ 11

136 ⫾ 16 83 ⫾ 12

0.004 0.01

6.7 ⫾ 3.1 10.8 ⫾ 5.1 8.5 ⫾ 4.8

4.9 ⫾ 0.4 7.2 ⫾ 2.4 5.2 ⫾ 1.3

0.0001 0.0001 0.0001

27 ⫾ 16 118 ⫾ 70 83 ⫾ 62 1.26 ⫾ 0.57 6.2 ⫾ 1.4 2.6 ⫾ 1.34 8.4 ⫾ 1.5 1.27 ⫾ 0.26 3.7 ⫾ 1.0

13 ⫾ 6 57 ⫾ 25 30 ⫾ 20 0.86 ⫾ 0.3 5.3 ⫾ 0.4 1.32 ⫾ 0.6 5.98 ⫾ 1.27 1.48 ⫾ 0.36 3.9 ⫾ 1.0

0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 NS 0.0005 NS

NS, not significant.

calculated by ␹2 test. A p value of ⬍0.05 was considered statistically significant. SAS was used as statistical software (SAS Institute, Cary, NC).

Results Baseline Patient Characteristics and Effect of Weight Loss on Metabolic Parameters Baseline patient characteristics and postoperative values are given in Table 1A. Weight loss within 14 ⫾ 5 months after gastroplasty was 45.2 ⫾ 2.4 kg, resulting in a decrease of 16 ⫾ 0.8 kg/m2 of BMI. This decrease in body weight was accompanied by a significant improvement in parameters of the metabolic syndrome including blood pressure, hyperglycemia, hyperinsulinemia, and dyslipidemia. Of 37 morbidly obese patients, 16 (43%) showed impaired glucose tolerance, and 14 (38%) suffered from type 2 diabetes. A normalization of glucose metabolism was induced by weight loss in 50% of patients preoperatively classified as having impaired glucose tolerance/type 2 diabetes (␹2: p ⬍ 0.001; Table 1B). 952


Inducers of TF in Obesity and Associated Metabolic Syndrome A correlation between TGF␤-1 and circulating TF, as well as hyperglycemia, hemoglobin A1c (HbA1c), and hyperlipidemia, was observed for the entire cohort of morbidly obese patients at baseline. However, after correction for multiple testing according to Bonferroni Holm, only the

Table 1B. Effect of weight loss on glucose tolerance status

IGT/DM (n) NGT (n)

Preoperative

Postoperative

30 7

15 22

␹2 ⬍ 0.001. IGT/DM, impaired glucose tolerance/type 2 diabetes; NGT, normal glucose tolerance.


Table 2A. Hemostatic parameters before and after gastroplasty

Table 2B. Inducers of TF-dependent coagulation before and after gastroplasty

Preoperative Postoperative p (n ⴝ 37) (n ⴝ 37) Value TF (pg/mL) Factor VII (ng/mL) F1.2 (nM) Total TFPI (ng/mL) Free TFPI (ng/mL) Prothrombin time (s) APTT (s) Fibrinogen (␮M) Platelet count (g/L)

314 ⫾ 181 130 ⫾ 22 2.4 ⫾ 3.4 69 ⫾ 17 48 ⫾ 12 99 ⫾ 6 34 ⫾ 4 11 ⫾ 2 275 ⫾ 44

235 ⫾ 113 113 ⫾ 19 1.14 ⫾ 1.1 64 ⫾ 15 44 ⫾ 12 94 ⫾ 12 34 ⫾ 3 10.3 ⫾ 2.2 261 ⫾ 51

0.041 0.023 0.039 0.036 0.037 0.012 NS 0.019 NS

APTT, activated partial thromboplastin time; NS, not significant.

correlation between TGF␤-1 and cholesterol remained significant (r ⫽ 0.44, p ⫽ 0.03). No correlation was observed between circulating TF and IL-6, although IL-6 showed a significant correlation with parameters of the metabolic syndrome such as hyperglycemia (IL-6 vs. fasting glucose: r ⫽ 0.58, p ⫽ 0.012; IL-6 vs. HbA1c: r ⫽ 0.6, p ⫽ 0.008) and hyperlipidemia (IL-6 vs. TG: r ⫽ 0.5, p ⫽ 0.007). Furthermore, no correlation was observed between TF and hsCRP or leptin, which correlated with selected parameters of the metabolic syndrome (hsCRP vs. fasting insulin: r ⫽ 0.43, p ⫽ 0.03; hsCRP vs. C-peptide: r ⫽ 0.56, p ⫽ 0.045; leptin vs. fasting glucose: r ⫽ ⫺0.48, p ⫽ 0.06; leptin vs. HbA1c: r ⫽ ⫺0.48, p ⫽ 0.07).

Preoperative Postoperative (n ⴝ 37) (n ⴝ 37) TGF␤-1 (pg/mL) Leptin (ng/mL) IL-6 (ng/mL) hsCRP (mg/L)

16.7 ⫾ 6.7 77.4 ⫾ 27.1 8.9 ⫾ 5.3 11 ⫾ 10

16.8 ⫾ 7.4 29.0 ⫾ 21.4 5.7 ⫾ 3.9 5⫾9

p Value NS 0.0001 0.019 0.001

NS, not significant.

TF Pathway and Glucose Tolerance in Morbidly Obese Patients Circulating plasma TF, cofactor VII, TGF␤-1, and hsCRP were significantly higher or exhibited a trend toward increased concentrations in morbidly obese patients with impaired glucose tolerance or type 2 diabetes compared with obese subjects with normal glucose tolerance at baseline; IL-6 was not different. Total and free TFPI as well as leptin were lower in subjects with type 2 diabetes compared with those who had impaired glucose tolerance (Table 3A). Baseline and postoperative values of plasma TF in obese patients with normal and impaired glucose tolerance or type 2 diabetes are shown in Table 3B. Weight loss reduced TF significantly in obese patients with impaired glucose tolerance. Neither a significant difference between pre- and postoperative values nor a significant postoperative decrease was observed for total or free TFPI when the cohort was separated into normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes (data not shown).

Discussion Effect of Weight Loss on TF and Procoagulant Activity in Morbidly Obese Patients Weight loss was associated with a significant reduction of circulating TF, the TF cofactor coagulation factor VII, and F1.2 (Table 2A). Circulating TF significantly correlated with in vivo thrombin formation as measured by prothrombin fragment F1.2, both preoperatively (r ⫽ 0.57, p ⫽ 0.008) and during the postoperative decrease (r ⫽ 0.56, p ⫽ 0.005). Prothrombin time and fibrinogen were reduced 14 ⫾ 5 months after operation. Both total and free TFPI significantly decreased after gastroplasty (Table 2A). Effect of Weight Loss on Potential Inducers of TF in Obesity Potential inducers of TF such as hsCRP, IL-6, and leptin significantly decreased with loss of body weight, whereas TGF␤-1 showed no significant systemic change with weight reduction (Table 2B).

Obese patients with associated metabolic syndrome are at increased cardiovascular risk (12,28). With respect to thromboregulation, a hypofibrinolytic state has been diagnosed in obese patients because of an elevated level of plasminogen activator inhibitor (4,29). A direct prothrombotic state mediated by increased procoagulant TF has been demonstrated in a mouse model for obesity (3,30,31) but not in obese humans. In this study, we show high-level procoagulant TF circulating in the plasma of obese patients, in particular in those with impaired glucose tolerance. The net procoagulant activity of elevated plasma TF in this cohort of morbidly obese patients was demonstrated by the positive correlation with prothrombin fragment F1.2, a split product of in vivo thrombin formation. Furthermore, the plasma level of coagulation factor VII, the cofactor of TF needed to form the binary catalytic complex TF/VII (a) (32), was increased in obese patients compared with reference values of healthy, normal weight subjects. OBESITY RESEARCH Vol. 11 No. 8 August 2003

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Table 3A. Inducers of the TF pathway in obesity with normal and impaired glucose tolerance or type 2 diabetes

TF (pg/mL) Factor VII (ng/mL) F1.2 (nM) Total TFPI (ng/mL) Free TFPI (ng/mL) Fibrinogen (mg/dL) Platelet count (g/L) TGF␤-1 (pg/mL) Leptin (ng/mL) IL-6 (ng/mL) hsCRP (mg/dL)

NGT (n ⴝ 7)

IGT (n ⴝ 16)

176 ⫾ 58 114 ⫾ 23 2.3 ⫾ 2.9 77.3 ⫾ 27.5 51 ⫾ 18 367 ⫾ 64 266 ⫾ 51 12.9 ⫾ 4.4 82.3 ⫾ 31.9 8.0 ⫾ 8.2 0.6 ⫾ 0.5

402 ⫾ 142§a 133 ⫾ 26 2.7 ⫾ 4.2 73.3 ⫾ 11.7 52.0 ⫾ 8.6 383 ⫾ 79 282 ⫾ 39 17 ⫾ 7.2*a 86.8 ⫾ 25.8 6.3 ⫾ 2.5 1.1 ⫾ 1.3

DM (n ⴝ 14) 294 ⫾ 214 136 ⫾ 13†a 2.1 ⫾ 2.7 59.5 ⫾ 7.6*b 41.2 ⫾ 8.5*b 375 ⫾ 60 271 ⫾ 47 18.1 ⫾ 6.9†a 63.6 ⫾ 21.4†b 10.8 ⫾ 9.0 1.4 ⫾ 0.8†a

NGT vs. IGTa, NGT vs. DMa, IGT vs. DMb: *p ⬍ 0.1, †p ⬍ 0.05, ‡p ⬍ 0.01, §p ⬍ 0.001. NGT, normal glucose tolerance; IGT, impaired glucose tolerance; DM, type 2 diabetes; NS, not significant.

TF and TGF␤-1 were elevated in morbidly obese patients with impaired glucose tolerance/type 2 diabetes compared with obese patients with normal glucose tolerance, and TGF␤-1 positively correlated with hypercholesterolemia, suggesting a potential role of TGF␤-1 as a link between the metabolic syndrome and TF expression in obese humans. This is in line with the leptin-deficient (ob/ob) obese mouse model, in which an increased level of TF expression has been demonstrated in the presence of increased TGF␤-1 mRNA expression (30). Baseline total and free TFPI were lowered in obese patients with type 2 diabetes compared with those who had impaired glucose tolerance. This is in accordance with previous studies that showed a significant difference between diabetic and nondiabetic patients with respect to pro- and anticoagulant parameters of the tissue factor pathway and in agreement with the concept of prediabetic endothelial damage (33–35). Our study showed a significant decrease of plasma TF—a surrogate marker of atherothrombosis and cardiovascular

risk— because of weight loss in obese patients and in particular in those with impaired glucose tolerance. These data suggest that a TF-dependent procoagulant state is associated with obesity and is reversed by weight control. The significance in the decrease of total and free TFPI associated with weight reduction may be interpreted as improvement of endothelial dysfunction with normalization of glucose metabolism (33); however, the significance disappeared because of the small sample size in subgroup analysis when stratified according to glucose tolerance. With respect to TF induction, proinflammatory cytokines may play a differential role in obese patients depending on the individual state of glucose tolerance. In obese patients with type 2 diabetes, TGF␤-1 and hsCRP were elevated compared with obese patients with normal glucose tolerance. In the entire cohort, TGF␤-1 correlated with both plasma TF and parameters of the metabolic syndrome. However, in normoglycemic obese patients, no correlation was found between TGF␤-1 and TF (r ⫽ 0.45, p ⫽ 0.45),

Table 3B. TF in obese patients with normal and impaired glucose tolerance or type 2 diabetes

NGT IGT DM

Preoperative

Postoperative

⌬

p Value

176.2 ⫾ 58.2 402.6 ⫾ 141.6† 294.3 ⫾ 214.2

257.4 ⫾ 102.5 237.9 ⫾ 104.0 220.6 ⫾ 134.9

⫺81.2 ⫾ 31.4 164.7 ⫾ 51.4* 73.7 ⫾ 62.2

NS 0.009 NS

NGT vs. IGT, NGT vs. DM: *p ⬍ 0.05, †p ⬍ 0.001. NGT, normal glucose tolerance; IGT, impaired glucose tolerance; DM, type 2 diabetes; NS, not significant.

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but significant correlation was found between TF and hsCRP (r ⫽ 0.9, p ⫽ 0.002), suggesting differential regulation of TF expression in obese patients with normal and pathological glucose metabolism. Hyperglycemia and glycated proteins were previously shown to induce monocyte TF, presumably by generating reactive oxygen species (36). Based on our data, it is tempting to speculate that hyperglycemia may mediate the expression of TF by induction of TGF␤-1 in adipose tissue as described previously in kidney cells in vitro (37). Weight loss induced by gastroplasty decreased parameters of the TF pathway as well as circulating proinflammatory parameters, lowered the systolic and diastolic blood pressure, and resulted in a significant improvement in the glucose- and lipid-metabolism in morbidly obese patients. Surprisingly, we did not observe a direct correlation between the decrease of TF and the postoperative change of IL-6. This may be, in part, because of the paracrine mechanism of adipocyte-derived proinflammatory cytokines (31,38). Although it is generally accepted that obese patients with BMI ⬎40kg/m2 have up to 50 –70% body fat (39,40), the lack of individual measurements is a limitation of this study. An increase in sample size would be necessary for correlative analysis among different subgroups of glucose tolerance. However, our study showed a significant decrease of the TF-dependent procoagulant state in morbidly obese patients after weight loss induced by gastroplasty, which may contribute to a reduction in cardiovascular risk.

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