Recent clinical and investigational applications of fibrin sealant in selected surgical specialties.
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Fibrin Tissue Adhesive↗
Biomedical subjects
Jeffrey H Lawson
Publications and source records attributed to Jeffrey H Lawson.
Coagulopathy and inflammation in neonatal heart surgery: mechanisms and strategies.
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Anticoagulants↗
Stem cell use in a patient with an ischemic foot ulcer: a case study.
Stem cell research has been discussed in both the political and popular arenas lately. Some types of stem cell research are controversial; however, not all stem cell research involves harvesting cells from an embryo or an aborted fetus. Another type of stem cell, the adult stem cell, resides within tissues and organs of the body and is responsible for repair after injury. Recent interest has focused on using adult stem cells isolated from a patient's bone marrow to stimulate the development of new blood vessels (a process called angiogenesis) in patients with peripheral vascular disease. These specialized stem cells are referred to as endothelial progenitor cells (EPCs). In laboratory and clinical studies it has been shown that these EPCs are involved in arterial repair and remodeling, as well as angiogenesis. The following case presentation will show how a patient with an ischemic toe ulcer and rest pain, who had no options for conventional revascularization, benefited from the injection of stem cells into her calf muscle. The process of angiogenesis using EPCs will be examined discussing the screening criteria and possible adverse events. The patient's history and progress throughout the recovery period will be reviewed.
Aged↗
The clinical use and immunologic impact of thrombin in surgery.
Thrombin is a naturally derived enzyme that has been widely characterized for its roles in hemostasis, inflammation, and cell signaling. Thrombin has been purified from numerous sources and used as a clinical aid for topical hemostasis for more than 60 years. Due to both its ease of use and apparent effectiveness, thrombin has become used routinely as an aid for topical hemostasis in nearly all types of surgical procedures, including but not limited to cardiovascular, orthopedic, neurologic, general, gynecologic, and dental procedures. Due to the widespread acceptance of thrombin in the surgical setting, it is conservatively estimated that at least 1 million patients in the United States are treated with topical applications of thrombin each year. Although the U.S. Food and Drug Administration (FDA) has approved a wide array of topical and biologic products to stop surgical bleeding, the only thrombin that is currently FDA approved as a stand-alone hemostatic product in the United States is derived from bovine sources. Bovine-derived thrombin has potent biologic activity in its ability to convert fibrinogen to fibrin, activate platelets, and induce vascular contraction. However, it has also been shown to induce a robust immune response following human exposure. Numerous reports have documented an array of clinical events that follow bovine thrombin exposure, which include the development of antibodies against thrombin, prothrombin, factor V, and cardiolipin. In some well-described cases, these antibodies have led to clinical syndromes that range from severe postoperative bleeding to high rates of vascular bypass graft thrombosis. Furthermore, experimental applications of bovine thrombin to various strains of mice have induced a postexposure autoimmune syndrome that was pathologically identical to lupus. Thrombin-derived products are well accepted by the surgical community for use as an aid for hemostasis, but the bovine-derived products have an unacceptably high and unnecessary association with immunologic side effects. If a nonimmunologic and effective thrombin were developed, one would expect it to be rapidly adopted by the clinical community.
Animals↗
The coagulopathy of trauma versus disseminated intravascular coagulation.
The coagulopathy of trauma is a syndrome of non-surgical bleeding from mucosal lesions, serosal surfaces, and wound and vascular access sites associated with serious injury, hypothermia, acidosis, hemodilution, and occasionally with classic disseminated intravascular coagulation (DIC). It can be largely explained by the effects of cold on platelet function, the effect of pH on coagulation factor activity, and the dilutional effects of resuscitation fluids and conventional blood products. DIC occurs acutely after trauma when brain, fat, amniotic fluid, or other strong thromboplastins enter the circulation. It occurs subacutely when endothelial inflammation or failure reduces clearing of activated coagulation factors allowing microthrombi to cause secondary injury. The coagulopathy of trauma should be anticipated in massive transfusion situations. Early treatment with plasma can delay its onset. The underlying mechanisms should be confirmed with laboratory testing.
Blood Coagulation Disorders↗
Reduction of vascular intimal-medial hyperplasia in polytetrafluoroethylene arteriovenous grafts via expression of an inhibitor of G protein signaling.
Polytetrafluoroethylene (PTFE) arteriovenous (AV) grafts are performed routinely for vascular access. The limited life span of PTFE grafts is a major cause of morbidity. Graft failure is attributed to venous outflow tract vascular smooth muscle (VSM) hyperplasia, which is linked to heterotrimeric G protein signaling. We proposed that expression of a peptide inhibitor of G(betagamma) signaling (betaARKct) in the venous outflow of PTFE grafts would reduce hyperplasia and prolong graft patency. Left carotid to right external jugular vein PTFE AV grafts were placed in swine. The isolated external jugular vein was treated with an adenovirus encoding betaARKct, empty adenovirus, or phosphate-buffered saline for approximately 25 min. After 7 or 28 days, flow probe analysis was performed and the vein was harvested and analyzed for cross-sectional area comparison. After both 7 and 28 days, when compared to controls, treated animals demonstrated a statistically significant reduction in VSM hyperplasia with a reduction in cross-sectional intimal and medial areas of >40% (p < 0.05). Flow was maintained in treated grafts, while control groups demonstrated a >50% reduction (p < 0.05) at 7 days. Further, treated grafts demonstrated significant improvement in graft patency at 28 days (100% vs. 12% for treated and untreated grafts, respectively). The inhibition of G(betagamma) signaling reduces intimal-medial hyperplasia and prolongs graft patency in PTFE AV grafts. This represents a novel molecular therapeutic strategy for improving the patency of vascular access grafts.
Anatomy, Cross-Sectional↗
Antihuman factor V antibodies after use of relatively pure bovine thrombin.
Although bovine thrombin is commonly used in the operating room, there is evidence that exposure to bovine thrombin can result in the development of autoimmune antibodies, usually against factor V, which can lead to a profound coagulopathy. It is thought that impurities in bovine thrombin preparations are responsible for the adverse reactions in patients. Here we describe a case in which exposure to a relatively pure bovine thrombin preparation resulted in the development of an antihuman factor V antibody-associated coagulopathy. This report calls into question the safety of even relatively pure bovine thrombin.
Aged↗
Multicenter evaluation of the bovine mesenteric vein bioprostheses for hemodialysis access in patients with an earlier failed prosthetic graft.
BACKGROUND: The number of patients requiring hemodialysis increases each year, with a large cohort of patients still requiring prosthetic grafts for hemodialysis. All available prosthetic vascular access grafts have predictable failure rates, leading to a large group of patients with multiple failed access grafts. This report evaluates use of mesenteric vein bioprosthesis (MVB) as a conduit for patients who have failed at least one earlier synthetic vascular access graft. STUDY DESIGN: Two-hundred seventy-six access grafts were implanted in patients who had at least one earlier failed synthetic graft. Of these grafts, 183 were MVB and 93 were synthetic. Graft histories were obtained from 128 of the 183 patients who received the MVB, representing a nonrandomized historic data set of previously failed grafts as an internal control group (INT). Patency was determined by Kaplan-Meier analysis, and the Cox proportional hazards model was used for multivariate analysis of factors predictive of effect. RESULTS: Primary patency at 12 months was 35.6% MVB versus 28.4% synthetic grafts. At 24 months, secondary patency was 60.3% MVB, 42.9% synthetic, and 18.0% INT (p < 0.0001, log- rank). Complication rates, including dilation, seroma, infection, and thrombosis, were all notably lower for the MVB compared with synthetic grafts by Cox regression (p < 0.001). Intervention rate per patient year was lower in the MVB group (0.97 versus 1.37) compared with synthetic grafts (p = 0.003). CONCLUSIONS: MVB provided superior secondary graft patency compared with both historic graft data or newly implanted nonrandomized synthetic implants. A considerable reduction in thrombosis, infection, and interventions was observed with the MVB graft. These results suggest that MVB offers a safe alternative to patients who have a history of failing synthetic access grafts and may represent an option for extending vascular access to this patient population.
Adolescent↗
Giant cell arteritis manifesting as mesenteric ischemia.
We report a case of giant cell arteritis in an 80-year-old woman who presented with chronic mesenteric ischemia to our vascular surgery service. Computed tomography, arteriography, and magnetic resonance angiography revealed long, smooth stenosis of the superior mesenteric artery and focal stenosis of the celiac artery. After the patient was found to have an elevated erythrocyte sedimentation rate and a positive temporal artery biopsy specimen, glucocorticoid therapy was initiated. Giant cell arteritis is a rare and easily overlooked cause of vascular insufficiency that can result in a devastating clinical outcome if not recognized before surgical therapy or other interventions are attempted.
Aged↗
Design of the Dialysis Access Consortium (DAC) Aggrenox Prevention Of Access Stenosis Trial.
BACKGROUND: Surgically created arteriovenous (AV) grafts are the most common type of hemodialysis vascular access in the United States, but fail frequently due to the development of venous stenosis. The Dialysis Access Consortium (DAC) Aggrenox Prevention of Access Stenosis Trial tests the hypothesis that Aggrenox (containing dipyridamole and aspirin) can prevent stenosis and prolong survival of arteriovenous grafts. METHODS: This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1056 subjects over four years with one-half year follow-up. Subjects undergoing placement of a new AV graft for hemodialysis are randomized to treatment with Aggrenox or placebo immediately following access surgery. The primary outcome is primary unassisted patency defined as the time from access placement until thrombosis or an access procedure carried out to maintain or restore patency. The major secondary outcome is cumulative access patency. Monthly access flow monitoring is incorporated in the study design to enhance detection of a hemodynamically significant access stenosis before it leads to thrombosis. RESULTS: This paper describes the key issues in trial design, broadly including: 1) ethical issues surrounding the study of a clinical procedure that, although common, is no longer the clinical intervention of choice; 2) acceptable risk (bleeding) from the primary intervention; 3) inclusion of subjects already receiving a portion of the study intervention; 4) inclusion of subjects with incident rather than prevalent qualifying clinical conditions; 5) timing of the study intervention to balance safety and efficacy concerns; and 6) the selection of primary and secondary study endpoints. CONCLUSIONS: This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent AV graft stenosis and failure, an important and costly problem in this patient population. Numerous design issues were addressed in implementing the trial and these will form a roadmap for future trials in this area.
Algorithms↗
Design of the Dialysis Access Consortium (DAC) Clopidogrel Prevention of Early AV Fistula Thrombosis Trial.
BACKGROUND: The Dialysis Access Consortium (DAC) was developed to investigate interventions to improve hemodialysis vascular access outcomes. The autogenous arteriovenous fistula created by direct connection of native artery to vein is the recommended vascular access for hemodialysis. However, it fails frequently due to clotting after surgery. PURPOSE: The DAC Early AV Fistula Thrombosis Trial tests the hypothesis that clopidogrel can prevent early fistula failure and increase the number of fistulas that ultimately become usable for hemodialysis access. This is one of two initial and concurrent trials being performed by the DAC. The companion trial investigates pharmacologic approaches to prevent venous stenosis leading to AV graft failure. METHODS: This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1,284 patients over four years. Patients undergoing creation of a new native arteriovenous (AV) fistula are randomized to treatment with clopidogrel or placebo for six weeks following fistula creation surgery. The primary outcome is fistula patency at six weeks. The major secondary outcome is fistula suitability for dialysis. RESULTS: This paper examines key aspects of this study that have broad relevance to trial design including: 1) the selection of an intermediate event as the primary outcome, 2) timing of the intervention to balance efficacy and safety concerns, 3) ethical considerations arising from required modifications of concomitant drug therapy, and 4) choosing an efficacy or effectiveness evaluation of the intervention. CONCLUSIONS: This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent early AV fistula failure and promote more usable fistulas for hemodialysis. The methodologic challenges identified and addressed during the development of this trial should help to inform the design of future vascular access trials, and are relevant to clinical trials addressing a wide range of questions.
Arteriovenous Shunt, Surgical↗
Challenges for providing effective hemostasis in surgery and trauma.
Vascular injury, whether surgical or traumatic, triggers a complex series of regulatory events. The understanding of these events, their interdependence, and their effect on hemostasis and thrombosis, is slowly being unraveled. The current understanding of these processes is reviewed in this paper. The application of this knowledge to the operating theatre has been slow and is severely limited by the lack of effective tools to monitor the coagulopathic status of individual patients. Hence, the initial treatment of patients with severe hemorrhage relies on improving the patient's physiological status and on basic surgical techniques. Should these efforts fail, then a number of topical hemostatic agents, selective inhibitors of fibrinolysis, and procoagulant molecules, such as recombinant factor VIIa, may be utilized. However, many of these agents have not yet been tested in clinical trials and studies are urgently needed to determine efficacy, safety, optimal dosage and time of administration.
Anticoagulants↗
Protease-activated receptor-2 signaling triggers dendritic cell development.
Dendritic cells (DC) are potent antigen-presenting cells that govern the effector cell responses of the immune system. DC are thought to continuously develop from circulating progenitors in a process that is accelerated by inflammatory stimuli. However, the physiological signals that regulate the development of DC from precursor cells have not been well defined. Here we show that a serine protease acting via protease-activated receptor-2 (PAR-2) stimulates the development of DC from bone marrow progenitor cells cultured in granulocyte-macrophage colony-stimulating factor and IL-4. DC fail to develop in bone marrow cultures treated with soy bean trypsin inhibitor, a serine protease inhibitor, but this inhibition is overcome by a PAR-2 agonist peptide. DC do not spontaneously develop from the bone marrow of PAR-2-deficient mice, but can be stimulated to do so by inflammatory mediators. These results suggest that endogenous serine proteases stimulate DC development in vitro. Thus, serine proteases may help trigger adaptive immune responses in vivo.
Animals↗
Hypercoagulable states and antithrombotic strategies in recurrent vascular access site thrombosis.
Vascular access site thrombosis is a major cause of morbidity in patients receiving hemodialysis. The role of hypercoagulable states in recurrent vascular access site thrombosis remains poorly understood. Data are limited regarding systemic anticoagulation to improve access graft patency, because of concern about hemorrhagic complications. We determined the prevalence of hypercoagulable states and clinical outcome (thrombotic and hemorrhagic) after initiation of antithrombotic therapy in a series of patients with recurrent vascular access site thrombosis. We evaluated 31 patients who had sustained 119 thrombotic events that resulted in vascular access graft failure during the year before evaluation. Sixty-eight percent of patients tested had elevated concentrations of antibody to anticardiolipin or topical bovine thrombin, and 18% of patients tested had heparin-induced antibodies. More than 90% of patients had elevated factor VIII concentration, 62% had elevated fibrinogen concentrations, and 42% had elevated C-reactive protein concentrations. Twenty-nine patients were given antithrombotic therapy: 13 with warfarin sodium, 12 with unfractionated heparin (UFH), and 11 with low molecular weight heparin (LMWH). Seven patients received more than one antithrombotic agent, sequentially. Nineteen patients have had no thrombotic events since beginning antithrombotic therapy (10 with warfarin, 3 with UFH, 6 with LMWH). Mean follow-up was 8.6 months (median, 7 months). Eight patients sustained 10 bleeding complications (5 with warfarin, 3 with UFH, and 2 with LMWH). In conclusion, hypercoagulable states are common in patients with recurrent vascular access site thrombosis. Antithrombotic therapy may increase vascular access graft patency, but is associated with significant risk for hemorrhage. Prospective studies are needed to evaluate the role and safety of antithrombotic agents in improving vascular access graft patency.
Adult↗
Relative purity of thrombin-based hemostatic agents used in surgery.
BACKGROUND: Hemostatic agents used in surgery contain thrombin isolated from either a bovine or human source. The use of thrombin derived from a bovine source has been associated with the development of an abnormal immune response, but a study of the immunoreactivity of the various commercially available thrombin preparations has not been conducted. This study determined the relative purity of commercially available thrombin preparations, if humans have natural antibodies that recognize these preparations, and if elicited antibodies against bovine thrombin cross-react with other bovine or human hemostatic agents. STUDY DESIGN: The purity of hemostatic agents was determined by protein and substrate assays, electrophoresis, and immunoblotting. The natural antigenicity and cross-reactivity of elicited antibodies were measured by ELISA using serum samples from 82 donors from the Red Cross and serum collected from patients exposed to bovine thrombin, respectively. RESULTS: All of the bovine thrombin preparations were found to contain the xenogeneic carbohydrate galactosealpha1-3galactose. The natural antigenicity of the bovine thrombin preparations was greater than that of a human thrombin preparation and similar to that of porcine aortic endothelial cells. Antibodies elicited against bovine thrombin were found to cross-react with other bovine preparations and other xenoantigens but not with human hemostatic preparations. CONCLUSIONS: All patients have antibovine thrombin antibodies, even before exposure to bovine thrombin-containing hemostatic agents. The cross-reactivity of elicited antibovine thrombin antibodies indicates that if a patient has been sensitized to a bovine product, it is likely safer to use a human-derived product in lieu of a bovine product.
Disaccharides↗
Human arteries engineered in vitro.
There is a pressing need to develop methods to engineer small-calibre arteries for bypass surgery. We hypothesized that the rate-limiting step that has thwarted previous attempts to engineer such vessels from non-neonatal tissues is the limited proliferative capacity of smooth muscle cells (SMCs), which are the main cellular component of these vessels. Ectopic expression of the human telomerase reverse transcriptase subunit (hTERT) has been shown recently to extend the lifespan of certain human cells. We therefore introduced hTERT into human SMCs and found that the resulting cells proliferated far beyond their normal lifespan but retained characteristics of normal control SMCs. Importantly, using these non-neonatal SMCs, we were able to engineer mechanically robust human vessels, a crucial step towards creating arteries of clinical value for bypass surgery.
Aorta↗
Gene therapy in tissue-engineered blood vessels.
Cardiovascular disease is the leading cause of morbidity and mortality in Western society. More than 1 million arterial bypass procedures are performed annually in the United States, where either autologous veins or synthetic grafts are used to replace arteries in the coronary or peripheral circulation. Tissue engineering of blood vessels from autologous cells has the potential to produce biological grafts for use in bypass surgery. Ex vivo development of vascular grafts also provides an ideal target of site-specific gene therapy to optimize the physiology of the developing conduit, and for the possible delivery of other therapeutic genes to a vascular bed of interest. In this article, we demonstrate that by using a novel retroviral gene delivery system, a target gene of interest can be specifically delivered to the endothelial cells of a developing engineered vessel. Further, we demonstrate that this technique results in stable incorporation of the delivered gene into the target endothelial cells for more than 30 days. These data demonstrate the utility of the retroviral gene delivery approach for optimizing the biologic phenotype of engineered vessels. This also provides the framework for testing an array of genes that may improve the function of engineered blood vessels after surgical implantation.
3T3 Cells↗
Fibrin sealant improves hemostasis in peripheral vascular surgery: a randomized prospective trial.
OBJECTIVE: To evaluate the efficacy and safety of an investigational fibrin sealant (FS) in a randomized prospective, partially blinded, controlled, multicenter trial. SUMMARY BACKGROUND DATA: Upper extremity vascular access surgery using polytetrafluorethylene (PTFE) graft placement for dialysis was chosen as a reproducible, clinically relevant model for evaluating the usefulness of FS. The FS consisted of pooled human fibrinogen (60 mg/mL) and thrombin (500 NIH U/mL). Time to hemostasis was measured, and adverse events were monitored. METHODS: Consenting adult patients (n = 48) undergoing placement of a standard PTFE graft were randomized in a 2:1:1 ratio to the treatment group using FS (ZLB Bioplasma AG, Bern, Switzerland), oxidized regenerated cellulose (Surgicel, Johnson & Johnson, New Brunswick, NJ), or pressure. Patients received heparin (3,000 IU IVP) before placement of vascular clamps. If the treatment was FS, clamps were left in place for 120 seconds after the application of study material to permit polymerization. If treatment was Surgicel, clamps were left in place until the agent had been applied according to manufacturer's instructions. If the treatment was pressure, clamps were released as soon as the investigator was ready to apply compression. Immediately after release of the last clamp, the arterial and venous suture lines were evaluated for bleeding. The time to hemostasis at both the venous and arterial sites was recorded. RESULTS: Significant (P < or =.005) reduction in time to hemostasis was achieved in the FS group. Thirteen (54.2%) patients randomized to FS experienced immediate hemostasis at both suture lines following clamp removal compared to no patients using Surgicel or pressure. Only one patient (7.1%) in the Surgicel group and no patients in the pressure group experienced hemostasis at 120 seconds from clamp removal, compared to 13 (54.2%) patients for FS. Adverse events were comparable in all groups. There were no seroconversions. CONCLUSIONS: FS achieved more rapid hemostasis than traditional techniques in this peripheral vascular procedure. FS use appeared to be safe for this procedure.
Aged↗