Safety of recombinant human factor XIII in a cynomolgus monkey model of extracorporeal blood circulation.

Factor XIII (FXIII) is a thrombin-activated plasma coagulation factor critical for blood clot stabilization and longevity. Administration of exogenous FXIII to replenish depleted stores after major surgery, including cardiopulmonary bypass, may reduce bleeding complications and transfusion requirements. Thus, a model of extracorporeal circulation (ECC) was developed in adult male cynomolgus monkeys (Macaca fascicularis) to evaluate the nonclinical safety of recombinant human FXIII (rFXIII). The hematological and coagulation profile in study animals during and after 2 h of ECC was similar to that reported for humans during and after cardiopulmonary bypass, including observations of anemia, thrombocytopenia, and activation of coagulation and platelets. Intravenous slow bolus injection of 300 U/kg (2.1 mg/kg) or 1000 U/kg (7 mg/kg) rFXIII after 2 h of ECC was well tolerated in study animals, and was associated with a dose-dependent increase in FXIII activity. No clinically significant effects in respiration, ECG, heart rate, blood pressure, body temperature, clinical chemistry, hematology (including platelet counts), or indicators of thrombosis (thrombin:anti-thrombin complex and D-Dimer) or platelet activation (platelet factor 4 and beta-thromboglobulin) were related to rFXIII administration. Specific examination of brain, heart, lung, liver, and kidney from rFXIII-treated animals provided no evidence of histopathological alterations suggestive of subclinical hemorrhage or thrombosis. Taken as a whole, the results demonstrate the ECC model suitably replicated the clinical presentation reported for humans during and after cardiopulmonary bypass surgery, and do not suggest significant concerns regarding use of rFXIII in replacement therapy after extracorporeal circulation.

Mediastinal fibrin glue: hemostatic effect and tissue response in calves.

There is continued controversy regarding the effectiveness and potential adverse effects of fibrin glue. Thus, we chose to evaluate it in a model of experimental calf aortic valve replacement that has been previously well established. Concentrated fibrinogen and topical thrombin were sprayed to form a thin layer of fibrin glue over the mediastinal tissues of 20 consecutive calves undergoing aortic valve replacement. Chest tube outputs of these animals were compared with those of the preceding 20 consecutive calves undergoing aortic valve replacement without fibrin glue. All procedures were performed by the same surgeon, and no other technical changes were made between the two series. Total postoperative chest tube output (mean +/- standard error) was 553 +/- 50 mL for the calves treated with fibrin glue and 1,155 +/- 103 mL for the control calves (p less than 0.001). On histological examination of mediastinal tissues from 5 treated calves killed 6 weeks after operation, there was no evidence of inflammation, fibrosis, or residual fibrin. To our knowledge, this is the first controlled laboratory study to show that fibrin glue spray is an effective hemostatic agent and that it produces no long-term tissue reaction.

Fibrin glue for the treatment of persistent lymphatic drainage.

A 7-year-old girl underwent resection of an abdominal wall lymphangiomatous tumor. Postoperative serous drainage, up to 300 mL per day, developed despite application of external pressure to the wound. Thirty-three days after the initial procedure, fibrin glue was applied to the draining tract. Concentrated fibrinogen was prepared from one unit of blood donated by the patient's mother. Ten milliliters fibrinogen and 10 mL thrombin (1,000 U/mL) were injected simultaneously through the wound drain as it was slowly removed, and pressure was reapplied for 48 hours. No further drainage occurred, and at 2- and 14-week follow-up examinations the wound had healed normally without reaccumulation of fluid. Fibrin glue successfully sealed this persistently draining abdominal wall tract. It is a painless, safe, and effective biologic sealant, and when prepared from homologous plasma it carries a low risk of virus transmission.

Enhancement of CO2 laser microvascular anastomoses by fibrin glue.

Laser-assisted microvascular anastomoses (LAMA) are characterized by low early bursting strength and high aneurysm rates. The effects of fibrin glue on bursting strength (BS), patency, and aneurysm rate of LAMAs were compared to standard suture and laser anastomosis. Rat femoral arteries (0.9-1.1 mm) were anastomosed end-to-end by three methods: (1) conventionally with 8 to 10 interrupted 10-O nylon sutures; (2) 3 stay sutures and CO2 laser (spot size, 0.275 mm; pulse, 0.2 sec, 80 mW); and (3) cryoprecipitated fibrinogen, 35 mg/cc, crystallized thrombin, CaCl, 20 mg/cc, aprotinin (2000 kIU/cc) applied to weld site in conjunction with laser weld as in (2) above. Patency, aneurysms, and histology were evaluated at 3 weeks, and BS (mm Hg) was measured in six additional vessels at 1 and 24 hr. There was no statistically significant difference in patency rates. Both the suture and fibrin glue groups had significantly higher 1 and 24 hr bursting strengths (P less than 0.05) and significantly lower aneurysm rates (P less than 0.001) than standard laser. There was no significant difference in bursting strength between suture and fibrin glue groups. Histology in the fibrin glue group showed medial damage similar to the LAMA and calcification of aneurysmal vessels. Fibrin glue enhancement of LAMAs produces equal patency, higher early bursting strength, and fewer aneurysms at 3 weeks compared to conventional laser.

Fibrin glue vs. nylon in the anastomosis of rabbit fallopian tubes.

Fibrin glue was used in end-to-end tubal anastomosis on eight sexually mature female New Zealand white rabbits. The right fallopian tubes were anastomosed with 10/0 nylon and the left with fibrin glue (Tissucol). The animals were mated with males of proven fertility six weeks after surgery and killed two weeks later. The gestational sacs and corpora lutea on the right and left sides were counted separately and the nidation index calculated for each. The presence of adhesions was also evaluated. All the tubes were finally examined under a scanning electron microscope. The fibrin glue was satisfactory in terms of patency, pregnancy and morphology of the epithelium.

A comparison of isobutyl 2-cyanoacrylate glue, fibrin adhesive, and oxidized regenerated cellulose for control of needle hole bleeding from polytetrafluoroethylene vascular prostheses.

Prolonged anastomotic and needle hole bleeding from synthetic vascular prostheses is a common surgical problem in heparinized patients and in the patient with a coagulopathy. The relative effectiveness of various hemostatic agents has not previously been determined by controlled comparisons. In this study 6 mm polytetrafluoroethylene (PTFE) vascular prostheses were used to perform carotid-carotid and femorofemoral bypasses in eight heparinized dogs. The relative effectiveness of isobutyl 2-cyanoacrylate, fibrin adhesive, and oxidized regenerated cellulose was determined by application of these hemostatic agents to three sources of bleeding: arterial-PTFE anastomoses, PTFE-PTFE anastomoses, and 18-gauge needle holes in PTFE vascular prostheses. The mean time to hemostasis (MTH) was determined for each hemostatic agent. Although application of isobutyl 2-cyanoacrylate resulted in the shortest MTH in each experimental group, the reported inflammatory response that it induces and its possible carcinogenicity limits its availability for clinical use. Application of fibrin adhesive prepared from single-donor hepatitis-screened plasma resulted in a significantly shorter MTH in each experimental group when compared with oxidized regenerated cellulose. We recommend clinical use of fibrin adhesive to control needle hole and anastomotic bleeding from PTFE vascular prostheses.

Long-term study after perforation of the round window. Animal experiments using electric response audiometry.

The round-window membrane of the inner ear of the guinea pig was perforated with a platinum wire under ketamine-xylazine anaesthesia. The latency times of waves I and V (Jewett) increased to 0.6 ms at 100 dB click HL stimulus loudness. The interpeak latencies did not change (4.0-4.2 ms). At 60 dB CHL stimulus loudness, no responses were discernible. Closure of the membrane damage by adhesive fibrin tissue had no effect on the auditory nerve potentials or the brain-stem responses. Normal latency times of waves I-V were seen 7 days after perforation. There was no difference between the animals with repaired and unrepaired membrane damage. We observed spontaneous healing of the round-window membrane 7 days after perforation, and a normal organ of Corti.

Fibrin seal--an alternative to suture repair in experimental pulmonary surgery.

Fibrin seal (FS) a biological tissue adhesive was evaluated as a sealant of lung parenchyma. New Zealand White (NZW) rabbits underwent a right upper lobe wedge resection. The defect was repaired with FS, suture (S), or a combination of S and FS (SFS). Five rabbits from each treatment group were sacrificed on postoperative Days 1, 3, and 14. The ventilatory pressure required to produce air leak was measured and the wet weight of normal vs hemorrhagic lung tissue determined. Although leak pressure was lowest in FS on Day 1 (P less than 0.05), leak pressure was equal to S and SFS of Day 3 and highest on Day 14 (P less than 0.01). FS-treated lungs had less hemorrhagic tissue than S and SFS (P less than 0.0001). Microscopically S and SFS repairs had large areas of hemorrhagic necrosis while FS showed minimal changes. We conclude that FS is an effective sealant of lung parenchyma.

[Therapeutic results of ultrasonically-guided kidney cyst punctures]. / Therapeutische Ergebnisse der ultraschallgeführten Nierenzystenpunktion.

The behaviour of renal cysts following puncture was studied in 62 patients on whom a simple diagnostic puncture had been performed and on fourteen patients who, in addition, had some of their own blood injected into the cyst. Twenty-one patients (34%) of the first group and eight patients (57%) of the second group showed definite reduction in the size of the renal cyst after an average period of observation of fifteen months. In 7%, the cyst disappeared completely following puncture. Parapelvic cysts showed much less tendency to disappear than did cortical cysts. The results of injecting autologous blood are comparable with those of injecting lipid soluble contrast media as a sclerosing agent. Before surgical removal of a symptomatic renal cyst is contemplated, puncture and evacuation of the cyst with autologous blood injection is recommended.

Bone healing stimulated by plasma factor XIII. Osteotomy experiments in sheep.

Sheep had their right metatarsals osteotomized midshaft and stabilized by plate and screws. One group was injected with 1250 units of Factor Thirteen for 9 days postoperatively, and a control group received placebo injections. After 8 weeks, the bones were evaluated biomechanically, histomorphologically and by densitometry. The bones of the treated group had a significantly higher tensile strength than the bones of the control animals. The correlation of biomechanical and morphological results demonstrated that the tensile strength increased with an increasing number of osteons crossing the osteotomy gap. The hydroxyapatite content of the bone healing zone was 7.3 per cent higher for the treated bones than for the control bones.

Studies on prevention of intra-abdominal adhesion formation by fibrin sealant. An experimental study in rats.

The preventive effect of fibrin sealant on post-operative formation of peritoneal adhesions was investigated in rats. Intraperitoneal adhesion formation was induced with a standardized, sutured defect in the peritoneum. The influence of sealant thickness and lifetime was evaluated by application of a thin and a thick layer of fibrin sealant containing high or low concentration of antiplasmin. Assessment of adhesion formation one week post-operatively showed significantly less adhesion to the defects covered with the thick layer of sealant having high or low antiplasmin concentration as compared with defects having only a thin sealant layer or control rats without sealant.

Evaluation of fibrin sealing for cardiovascular surgery.

Hemorrhage remains a problem in patients undergoing cardiovascular surgery. To evaluate fibrin sealant, a completely biodegradable hemostatic agent, three series of experiments were performed in mongrel dogs. In series I, 18 dogs had a 7 cm interposition of knitted Dacron (water porosity 1500 ml/min/cm2) in the descending aorta. In group A, all prostheses were treated with fibrin sealant and in group B by blood preclotting. Measurements of blood loss demonstrated 1.29 +/- 0.26 ml/min in group A as compared with 30.16 +/- 2.85 ml/min in group B (p less than .001). In series II, six dogs of each group were compared for thrombogenicity and platelet survival by using indium-111-labeled autologous platelets. According to Goldman et al., the thrombogenicity index was calculated. The mean thrombogenicity index for group A was 0.23 +/- 0.02 in contrast to 0.33 +/- 0.05 for group B (p greater than .05). Mean platelet survival was 5.59 +/- 0.23 days in group A in contrast to 5.34 +/- 0.05 days in group B (p greater than .05). In series III, the gluing potential was investigated by creating four types of injuries: four dogs had an aortic stab wound 3 to 5 mm, six dogs received a 10 to 15 mm stab wound to the left ventricle, seven dogs had a 3 cm laceration of the left atrial appendage, and four dogs had bilateral division of their carotid arteries. Wounds of the aorta and left atrial appendage were treated by partial clamping and the sole use of fibrin sealant, the carotid arteries were repaired by four simple sutures and fibrin sealant, and the left ventricular stab wounds were treated by the combined use of heterologous collagen and fibrin sealant without suture.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined application of heterologous collagen and fibrin sealant for liver injuries.

Hemostasis in complex liver injuries remains a problem despite improvements in operative techniques including debridement, suturing or packing. To evaluate fibrin sealant (FS), a new biodegradable hemostatic agent in combination with porcine collagen for sealing of liver injuries, three series of experiments were performed in 132 rats. In series I, 18 rats had a 10-mm in diameter and 2-mm in depth punch defect to the left lateral lobe. In the FS group (n = 9), bleeding was treated by insertion of an FS-soaked piece of collagen of equal size which was firmly attached to a plastic disk with wire anchor. In the control group (n = 9), collagen alone was inserted. Fifteen minutes after the insertion the lobe was excised and pull-off experiments were performed with simultaneous script chart recording. There was a highly significant difference in the adhesion to the liver surface (85.6 +/- 7.1 in the FS group versus 24.8 +/- 2.6 g/cm2 in the control group, P less than 0.001). In series II, 42 anticoagulated rats (Coumadin, PT 27.5% +/- 1.3) with lobectomy or liver rupture were placed in three groups (n = 14). Group I was treated with FS, group II with FS and collagen, and group III with catgut sutures which served as controls. Fourteen days later 12 rats of group I, 13 of group II, and 7 of group III were alive yielding 85.7, 92.8, and 50% overall survival rates, P less than 0.05 groups I and II versus group III. In series III, 72 non-anticoagulated rats were treated identically to series II and examined morphologically at 1, 7, 28, and 56 days.(ABSTRACT TRUNCATED AT 250 WORDS)