Synergistic effects of INTERCEED(TC7)* and heparin in reducing adhesion formation in the rabbit uterine horn model†‡

Vol. 55, No.2, February 1991

FERTILITY AND STERILITY

Printed on acid-free paper in U.S.A.

Copyright <> 1991 The American Fertility Society

Synergistic effects of INTERCEED(TC7)* and heparin in reducing adhesion formation in the rabbit uterine horn modelt* Michael P. Diamond, M.D.§ II~# Cary B. Linsky, Ph.D.# Tim Cunningham# Lola Kamp, B.S.#

Eli Pines, Ph.D.# Alan H. DeCherney, M.D.§ Gere S. diZerega, M.D.**

Yale University School of Medicine, New Haven, Connecticut; Johnson and Johnson Medical, Inc., New Brunswick, New Jersey; and University of Southern California Medical Center, Los Angeles, California

Surgical adjuvants are commonly employed to reduce the frequency of postoperative adhesion development after reproductive pelvic surgery. The ability of indomethacin, promethazine, dexamethasone, Intralipid, progesterone, and heparin to reduce adhesion formation in combination with INTERCEED(TC7) (Johnson and Johnson Medical, Inc., New Brunswick, NJ), an absorbable barrier that alone reduces adhesion formation, was examined in a rabbit uterine horn model. A significant reduction in adhesion formation was only observed with the combination of INTERCEED(TC7) plus heparin. In additional studies, heparin delivery by intraperitoneal (IP) lavage, intravenous injection, or intra-abdominal instillation failed to demonstrate efficacy. Similarly, heparin delivery with other barriers or IP instillates (carboxymethylcellulose or 32% Dextran 70) failed to reduce adhesion formation. We conclude that INTERCEED(TC7) can be efficaciously utilized as a carrier to deliver heparin to traumatized surfaces, thereby reducing adhesion formation. Fertil Steril55:389, 1991

Received March 15, 1990; revised and accepted August 16, 1990. * Johnson and Johnson Medical, Inc., New Brunswick, New Jersey.

t Presented in part at the 43rd Annual Meeting of The American Fertility Society, Reno, Nevada, September 28 to 30, 1987; and at the 73rd Annual Meeting of The American College of Surgeons, San Francisco, California, October 11 to 16,1987. :j: Supported by Johnson and Johnson Medical, Inc., New Brunswick, New Jersey. § Department of Obstetrics and Gynecology, Yale University School of Medicine. II Recipient of the Clinical Associate Physician Award of the Yale General Clinical Research Center of the National Institutes of Health, Bethesda, Maryland.

\[ Reprint requests: Michael P. Diamond, M.D., Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, P. O. Box 3333, New Haven, Connecticut 06510. # Johnson and Johnson Medical, Inc., New Brunswick, New Jersey. ** Department of Obstetrics and Gynecology, University of Southern California Medical Center. Vol. 55, No.2, February 1991

Development of postoperative adhesions after reproductive pelvic surgery can seriously detract from the efficacy of these operative procedures. 1- 3 A wide variety of adjuvants are utilized in attempts to prevent the development of postsurgical adhesions. 4- 6 Recently, an absorbable barrier composed of oxidized regenerated cellulose, INTERCEED(TC7) (Johnson and Johnson Medical, Inc., New Brunswick, NJ) was shown to be efficacious in reducing adhesion formation in two rabbit models 7 ,8 and in a human clinical tria1. 9 However, INTERCEED(TC7) was unable to completely eliminate postoperative adhesions in all cases. The mechanism of action by which barriers can reduce adhesion formation relates, at least in part, to physical separation of interposing peritoneal surfaces. Potentially, a combination of INTERCEED(TC7) with pharmacological agents could improve efficacy of the barrier. In this manner, the barrier would act as a device for local drug delivery to the traumatized tissues. This report examines the application of a variety of surgical adjuvants delivered directly to the rabbit uterine horn by INTERCEED(TC7).

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MATERIALS AND METHODS

The rabbit uterine horn model was performed as previously described. 7 The study used five experimental groups. In the first experiment, substances tested were INTERCEED(TC7) and sodium heparin (Elkins/Sinn 1,000 USP units/mL) in a doseresponse format. INTERCEED(TC7) is a specially knitted pattern of oxidized regenerated cellulose. Rabbits were randomly assigned to one of four groups after creation of the uterine horn lesions: control (n = 16), INTERCEED(TC7) with 100 U heparin/horn (n = 12), INTERCEED(TC7) with 500 U heparin/horn (n = 9), and INTERCEED(TC7) with 1,000 U/horn (n = 28). The uterine horn scraping was performed in six separate surgical settings at the same center by the same surgeon (T.C.): not all groups were performed in each setting. In the groups treated with INTERCEED(TC7), each uterine horn was completely wrapped with a single layer ofthe barrier (approximately 5 X 71 em/horn). The INTERCEED(TC7) was placed in position while dry, and then moistened with 1 mL of saline or of the test concentration of heparin. All test solutions were diluted so that the prescribed amount of heparin was delivered in a volume of 1 mL/horn. In the second experiment, the study groups were untreated controls (n = 8); INTERCEED(TC7) and promethazine (Phenergan, Wyeth Laboratories, Philadelphia, PA, 25 mg/horn, n = 7); INTERCEED(TC7) and dexamethasone (DEX) (4 mg/horn, n = 7); INTERCEED(TC7) and progesterone (P) in peanut oil (Eli Lilly, Indianapolis, IN, 50 mg/horn, n = 7); INTERCEED(TC7) and indomethacin (Merck Sharp and Dohme, West Point, PA, 5 mg/horn, n = 6); INTERCEED(TC7) and corn oil (1 cc, n = 6); INTERCEED(TC7) and peanut oil (1 cc, n = 6); Intralipid 20 mL instillate/ rabbit (Kabi -Vitrum, Alameda, CA, n = 5); and Intralipid, 1 mL/horn, plus INTERCEED(TC7). In the groups treated with INTERCEED(TC7), 1 mL of the indicated solutions was applied to the material overlying the uterine horn. In the third experiment, rabbits were assigned to one of five groups: untreated controls (n = 17), Ringer's lactate lavage (n = 6), heparinized lavage (175 U/rabbit, n = 6), intraperitoneal (IP) heparin, (2,000 U, n = 6), and intravenous (IV) heparin (2,000 U, n = 6). This experiment was performed in four parts. The 175 U lavage was chosen to correspond on a per kilogram basis with the clinical practice of using 1 L of solution containing 5,000 U heparin/L. 390

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In experiment four, different delivery methods were evaluated; no adjuvant (control, n = 4); gelfoam (Upjohn, Kalamazoo, MI) alone (approximately 5 X 71 em/horn, n = 3); gelfoam plus 2,000 U heparin/horn, (n = 8); gelfilm (Upjohn, n = 2), carboxymethylcellulose (CMC, Hercules, Wilmington, DE, 20 cc of a 2% solution) plus 2,000 U heparin/horn (n = 6), and 32% Dextran 70 (Hyskon, Pharmacia, Piscataway, NJ, 20 mL) containing 2,000 U heparin/horn (n = 12). In experiment five, a direct comparison was made of the efficacy of INTERCEED(TC7) plus heparin (1,000 U/horn, n = 10) versus either INTERCEED(TC7) alone (n = 9) or control (n = 8) rabbits. After bilateral scraping of the uterine horns, animals were randomly assigned to one of the above three groups. Animals were evaluated for adhesion formation at necropsy 2 to 3 weeks after surgery. Scoring was performed in a blinded fashion with regard to treatment group. The evaluation utilized a previously described scoring system that considered both the extent and severity of the adhesions. 7 The scoring system utilized the presence of adhesions determined along the length of the traumatized area of the horn (5 em). Accordingly, the following grading system was used: 0, no adhesion; 1,25% of traumatized area; 2, 50% of traumatized area; 3, total involvement. Fractional scores were given for extent of adhesions intermediate between the above grades. The severity (tenacity) of the adhesions was measured as follows: 0, no resistance to separation; 0.5, some resistance (moderate force required); 1, sharp dissection needed. The total grade was additive giving a range of adhesion scores from o to 4, which represented both extent and severity. A previous study using this adhesion model has demonstrated no difference in adhesion formation scores when necropsy is performed at 2, 4, or 8 weeks after the initial operative procedure. 7 In all five experiments, adhesion scoring was conducted by an individual without prior knowledge of treatment group assignments. There was a small number of rabbits (see Results) in which the continued presence of adjuvants was identified at necropsy, thus preventing complete blinding of the adhesion scorer. Statistical analysis was performed using Kruskal-Wallis one-way ANOVA and x2 tests. The unit of measure for the ANOV A was the average adhesion score per animal. Additionally, Dunn's procedure for multiple comparisons among the control groups was performed. Statistical sig-

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~!

l r

Table 2 Adhesion Scores at Necropsy in Control Rabbits and Rabbits Treated With Adjuvants

Table 1 Adhesion Scores at Necropsy in Control Rabbits INTERCEED(TC7) Plus 100 USP U Heparin/Horn, ' INTERCEED (TC7) Plus 500 U Heparin/Horn, and INTERCEED(TC7) Plus 1,000 U Heparin/Horn No. of No.ofrabbits uterine with no horns adhesions Control INTERCEED(TC7) plus 100 U heparin/horn INTERCEED(TC7) plus 500 U heparin/horn INTERCEED(TC7) plus 1,000 U heparin/horn

Adhesion score/ horn"

32

0

3.6 ± 0.2

24

3

0.9 ± 0.2b

18

5

0.4 ± 0.2b

56

19

0.6 + 0.2b

" Values are means ± SEM. b ANOV A test statistic 34.95; P < 0.0001.

nificance was defined as P < 0.05. Data are expressed as means ± SEM.

No. of uterine horns

No. of rabbits with no adhesions

Adhesion score/ horn"

16

1

2.9 ± 0.4

14

0

3.3 ± 0.3

12

0

3.1 ± 0.3

14 10

0 0

3.9 ± 0.1 3.1 ± 0.4

10

0

3.7 ± 0.2

12

0

3.9 ± 0.1

12

0

4.0±0.0

14

0

4.0±0.0

Control Dexamethasone plus INTERCEED(TC7) Indomethacin plus INTERCEED(TC7) Promethazine plus INTERCEED(TC7) Intralipid Intralipid plus INTERCED(TC7) Corn oil plus INTERCEED(TC7) Peanut oil plus INTERCEED(TC7) Pin oil plus INTERCEED(TC7) • Values are means ± SEM.

RESULTS In the control rabbits, the average adhesion score in these experiments was not different (ANOVA test statistics, 5.55; P = 0.14) and was similar to the mean adhesion score previously reported for this model7 (experiment 1, 3.6 ± 0.2; experiment 2, 2.9 ± 0.4; experiment 3, 3.7 ± 0.2; and experiment 4,4.0 ± 0.0, and experiment 5, 3.5 ± 0.3). There were no intraoperative or postoperative complications attributable to INTERCEED(TC7) or heparin in any of the rabbits in the experiment. At the time of examination 2 weeks after the initial operative procedure, only scant «3 mm2 ) remnants of the INTERCEED(TC7) remained. Combination of heparin plus INTERCEED(TC7) significantly reduced the adhesion score compared with control rabbits (ANOVA test statistic 34.95, P < 0.0001, Table 1). Additionally, when examined as a function of the number of rabbits with no adhesions at necropsy, the combination of INTERCEED(TC7) with heparin improved efficacy in a dose-dependent fashion. At the highest dose of heparin, 1,000 USP U/horn, 68% ofrabbits (19 of 28) had no adhesions on either uterine horn as c?mpared with five of nine rabbits at 500 U heparm/horn, and only 3 of 12 rabbits at 100 U heparin/ horn (x 2 analysis, 6.237; P < 0.05). Thus, the addition of heparin to INTERCEED(TC7) reduced the incidence of adhesions as well as the adhesion scores in this model. Table 2 compares adhesion formation in the rabbit uterine horn model in control rabbits, rabbits treated with Intralipid, and those treated with INVol. 55, No.2, February 1991

TERCEED(TC7) in combination with DEX, indomethacin, Intralipid, corn oil, peanut oil, P in peanut oil, and promethazine. Compared with controls, there was no reduction in adhesion scores with any of these agents. Thus, combinations of other commonly utilized surgical adjuvants with INTERCEED(TC7) failed to reduce adhesion formation. Heparin was administered in several ways after abrasion of the uterine horns to assess whether the reduction in adhesion score that occurred when heparin was added to INTERCEED(TC7) was because of heparin per se (Table 3). Whether administered by IP lavage, IV infusion, or direct IP application, there was no reduction in adhesion scores below those of untreated rabbits. Furthermore, the group with direct IP heparin instillation and the group with INTERCEED(TC7) plus heparin had Table 3

Adhesion Scores at Necropsy in Control Rabbits or Treated by Ringer's Lactate Lavage, Heparinized Rmger s Lavage (175 USP Heparin/Rabbit), IV Heparin (2,000 USP /Rabbit), or IP Heparin (2,000 USP /Rabbit) R?bbit~

Control Ringer's lactate lavage Heparinized Ringer's lactate lavage IV heparin IP heparin

No. of uterine horns

No. of rabbits with no adhesions

Adhesion score/ horn"

34 12

0 0

3.7 ± 0.2 3.9±0.1

12 12 12

0 0 0

3.9 ± 0.1 4.0±0.0 3.6+0.3

" Values are means ± SEM.

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Table 4 Uterine Horn Adhesion Formation Scores in Control Rabbits and Rabbits Treated With INTERCEED(TC7) Alone or INTERCEED(TC7) Plus Heparin (1,000 U/Horn) No. of No. of rabbits uterine with no horns adhesions Control INTERCEED(TC7) INTERCEED(TC7) plus 1,000 U heparin/horn

Adhesion score/ horn a

16 18

o

o

3.5 ± 0.3 b 2.2 ± 0.3 b

20

7

0.6 ± 0.3 b,c

Values are means ± SEM. ANOVA test statistic 16.16, P < 0.001. c P < 0.05 vs INTERCEEED(TC7) alone.

a

b

heparin applied in the same manner. Yet in the former, 10 of 12 horns had maximum adhesion scores. Therefore, the mode of heparin delivery was important for adhesion reduction. To examine the effect of heparin delivery on adhesion formation to the uterine horns by other materials' heparin (2,000 Vjrabbit) was combined with gelfoam, gelfilm, CMC, or Hyskon. Two of 6 rabbits treated with CMC plus heparin died within 48 hours of surgery, whereas 3 of 12 treated with Hyskon (Pharmacia, Piscataway, NJ) plus heparin died within 24 hours of surgery. There were no postoperative deaths in any of the other groups. Gelfilm (Vpjohn) was not able to conform to the uterine horns and thus may not have delivered heparin to the injured sites. Gelfoam (Vpjohn) alone failed to reduce adhesion score (4.0 ± 0.0) from the control group score. Application of heparin to gelfoam covering the uterine horns (adhesion score 3.8 ± 0.1) also failed to reduce the adhesion scores. Similarly, combinations of heparin with either CMC (adhesion score 3.3 ± 0.5) or Hyskon (adhesion score 4.0 ± 0.0) did not significantly reduce adhesion scores. Therefore, delivery of heparin in these materials failed to reduce adhesion formation. In a subsequent study, a direct comparison of the ability of INTERCEED(TC7) alone versus INTERCEED(TC7) plus heparin in reducing adhesion formation in the rabbit uterine horn model was performed. As shown in Table 4, INTERCEED(TC7) alone significantly reduced adhesion formation scores compared with the control group; the combination ofINTERCEED(TC7) plus heparin resulted in a further significant reduction in adhesion formation scores (ANOVA test statistic 16.16; P < 0.001), whether compared with the control group (P < 0.05) or to the rabbits treated with INTERCEED(TC7) alone (P < 0.05). 392

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DISCUSSION

This study examines the effect of a variety of commonly used surgical adjuvants on adhesion formation in a rabbit model. When these agents were applied directly to the traumatized surface, no reduction of adhesion formation was found with onetime administration of high doses of promethazine, DEX, indomethacin, Intralipid, or P. These findings are consistent with most previous studies of pharmacological adjuvants that have failed to reproducibly demonstrate a reduction in adhesion formation. 3- 6 In contrast to these agents were the effects observed when heparin was applied to the INTERCEED(TC7). At doses of 100, 500, and 1,000 Vj horn, INTERCEED(TC7) plus heparin significantly reduced adhesion formation scores compared with untreated controls or our previous report7 with treatment ofINTERCEED(TC7) alone. Additionally, in a direct comparison, treatment with INTERCEED(TC7) plus 1,000 V heparinj horn demonstrated a significantly greater reduction in adhesion formation than INTERCEED(TC7) alone (Table 4). These beneficial effects of heparin were not demonstrated when heparin was delivered by other routes, whether IV, IP, or by peritoneal lavage. Thus in the rabbit uterine horn model, heparin used together with INTERCEED(TC7) improves efficacy of INTERCEED(TC7) alone in reducing adhesion formation. This benefit appears to be because of a direct, local action of heparin on the deperitonealized surfaces. Adhesion development is thought to result from exudation of proteinaceous fluid including fibrin0gen from the site of peritoneal injury.lO Concomitantly, histamine is released, which further increases local exudation. The proteinaceous mass, including inflammatory cells and tissue debris, exists between adjoining structures. If this fibrin mass is not degraded, an adhesion develops. This occurs because of fibroblast ingrowth into the fibrin mass, with subsequent collagen deposition and vascular proliferation. This fibrin mass is thought to persist over 4 to 5 days,11,12 during which time reperitonealization from adjacent mesenchymal tissue is ongoing. The ability of INTERCEED(TC7) plus heparin to reduce adhesion formation is probably attributable to each constituent. INTERCEED(TC7) acts as a barrier to separate the traumatized surface from adjacent surfaces. After placement, this ma-

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terial gelates, thereby covering the deperitonealized tissue, reducing the likelihood of interconnecting fibrous bands. Continued presence of INTERCEED(TC7) may not be needed as long as it is present during the initial 4-day period during reperitonealization. Additionally, the INTERCEED(TC7) acts as a "carrier" to apply heparin directly to the traumatized surfaces. We hypothesize that such application could reduce congealing of the fibrinous masses in and around the INTERCEED(TC7), thus reducing fibrin "bridges" between adjoining structures into which fibroblasts could migrate later in the healing process, thereby further reducing adhesion development. Heparin per se actively reduces adhesions in human and animal studies. However, in the early studies utilizing heparin, the dose required to reduce adhesion formation resulted in hemorrhagic diathesis. Two recent studies used lower doses of heparin and noted beneficial results; one utilized IP instillation, and the other utilized continuous infusion over the traumatized site. 13,14 There are many mechanisms by which heparin may exert its beneficial effects. Heparin in combination with antithrombin III inhibits clotting by enhancing serine esterase activity, 15 thus reducing the deposition of fibrin strands that form the scaffold for fibroblast ingrowth. Second, heparin directly stimulates plasminogen activator activity,16,17 which would enhance fibrinolysis. Third, heparin binds to fibroblast growth factor, which stimulates wound healing. 18 Thus, the addition of heparin to INTERCEED(TC7) potentiates the beneficial effect of INTERCEED(TC7) alone. Heparin plus INTERCEED(TC7) results in a reduction in adhesion formation at the application site. However, in reproductive pelvic surgery, postoperative adhesion development is not limited to the primary surgical site, but frequently involves other traumatized, previously adhesion-free sites as well. 19 Thus it would be desirable to employ an adjuvant that would benefit other peritoneal sites as well as the primary site of surgery. A liquid like Hyskon or CMC would potentially coat peritoneal surfaces throughout the abdomen and have been shown in some, but not all studies, to reduce adhesion development. 4 In previous studies utilizing the rabbit uterine model, CMC was found to be efficacious in reducing adhesion formation; Hyskon was not. 20 In the present study, addition of heparin (2,000 U) to these solutions at the completion of the operative procedure did not reduce adhesion formation. Paradoxically, in the presence of hepaVol. 55, No.2, February 1991

rin, the reduction in adhesions in this model achieved with CMC alone was eliminated. Additionally, combination of CMC or Hyskon with heparin resulted in rabbit mortality rates of 33% and 25%, respectively, because of bleeding diatheses. Although we previously noted mortality with larger doses of CMC, CMC alone at this dose did not result in death.20 Both the failure to reduce adhesions and the mortality stemming from hemorrhage may be related to combination of the nonclotting actions of heparin with the mechanism of adhesion reduction postulated for these liquids. In addition to the well-recognized theories of lubricating and hydrofiotation effects,4 these agents are also fibrinolytic. 21 ,22 This, in combination with the actions of heparin could result in increased bleeding at the scraped surfaces of the uterine horns. Minimally, the combined effects of these agents could result in postoperative bleeding sufficient to increase deposition of fibrinous exudate, resulting in greater adhesion scores. In its more severe forms, postoperative bleeding from these sites could result in hemorrhagic shock and death. Combined use of these polyglycans with heparin does not appear warranted. A recent report of human application ofINTERCEED(TC7) demonstrated clinical efficacy in the reduction of postoperative adhesion development. 9 Further clinical trials will be needed to assess whether heparin in combination with INTERCEED(TC7) will be able to further reduce postoperative adhesion development in humans. Acknowledgments. The authors acknowledge the statistical review and assistance of Mr. Gil Henyon, Johnson and Johnson Medical, Inc., and the secretarial support of Ms. Joan Andrews, Yale University School of Medicine.

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prevention, and therapy. Clin Obstet Gynecol23:1201, 1980 2. Luciano AA, Hauser KS, Benda J: Evaluation of commonly used adjuvants in the prevention of postoperative adhesions. Am J Obstet Gynecol148:88, 1983 3. DeCherney AH: Preventing postoperative pelvic adhesions with intraperitoneal treatment. J Reprod Med 29:157,1984 4. Diamond MP, DeCherney AH: Pathogenesis of adhesion formation/reformation: application to reproductive surgery. Microsurgery 8:103,1987 5. Pfeffer WH: Adjuvants in pelvic surgery. Fertil Steril 33: 245,1980 6. Holtz G: Prevention and management of peritoneal adhesions. Fertil Steril41:497, 1984 7. Linsky CB, Diamond MP, Cunningham T, Constantine B,

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DeCherney AH, diZerega, GS: Adhesion reduction in a rabbit uterine horn model using TC-7. J Reprod Med 32:17, 1987 Diamond MP, Linsky CB, Cunningham T, Constantine B, diZerega GS, DeCherney AH: Development of a model for sidewall adhesions in the rabbit and their reduction by an absorbable barrier. Microsurgery 8:197, 1987 INTERCEED(TC7) Adhesion Barrier Study Group: Prevention of postsurgical adhesions by INTERCEED(TC7), an absorbable adhesion barrier: a prospective, randomized multicenter clinical study. Fertil Steril 51:933, 1989 diZerega GS, Holtz G: Cause and prevention of postsurgical pelvic adhesions. In Advances in Clinical Obstetrics and Gynecology, Edited by H Osofsky. Baltimore, Williams and Wilkins, 1982, p 277 Glucksman DL, Warren WD: The effect of topically applied cortico-steroids in the prevention of peritoneal adhesions: an experimental approach with review of the literature. Surgery 60:352, 1966 Orita H, Girgis W, diZerega GS: Prevention of postsurgical peritoneal adhesion formation by intraperitoneal administration of ibuprofen. Drug Developmental Res 10:97, 1987 Al-Chalabi HA, Otubo JAM: Value of a single intraperitoneal dose of heparin in prevention of adhesion formation: an experimental evaluation in rats. Int J FertiI32:332, 1987

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14. Holtz G: Prevention of postoperative adhesions. J Reprod Med 24:141, 1980 15. Fukasawa M, Girgis W, diZerega GS: Inhibition of postsurgical adhesions in a standardized rabbit model: Intraperitoneal treatment with heparin. Int J Fertil. In press 16. Rosenberg RD: Heparin antithrombin and abnormal clotting. Ann Rev Med 29:267, 1978 17. Andrade-Gordon P, Strickland S: Interaction of heparin with plasminogen activators and plasminogen: effects on the activation of plasminogen. Biochemistry 25:4033,1986 18. Markwardt F, Klocking HP: Heparin induced release of plasminogen activator. Haemostasis 6:370, 1977 19. Gospodarowicz D, Ferrara N, Schweigerer L, Neufeld G: Structural characterization and biological functions of fibroblast growth factor. Endocr Rev 8:95, 1987 20. Diamond MP, Daniell JF, Feste J, Surrey MW, McLaughlin DS, Friedman S, Vaughn WK, Martin DC: Adhesion reformation and de novo adhesion formation after reproductive pelvic surgery. Fertil Steril47:864, 1987 21. Diamond MP, DeCherney AH, Linsky CB, Cunningham T, Constantine B: Assessment of carboxymethylcellulose and 32% Dextran 70 for prevention of adhesions in a rabbit uterine horn model. Int J Fertil 33:278, 1988 22. Wagaman R, Ingram JM, Papineni SR, Hussain IS: Intravenous versus intraperitoneal administration of dextran in the rabbit: effects on fibrinolysis. Am J Obstet Gynecol155: 464, 1986

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