Fibrin sealant (evicel® [quixil®/crosseal™]): a review of its use as supportive treatment for haemostasis in surgery

Evicel? is a fibrin sealant consisting of two components, human clottable protein (predominantly human fibrinogen) and human thrombin. It is indicated as supportive treatment in patients undergoing surgery when control of bleeding by standard surgical techniques is ineffective or impractical. Evicel? is a new formulation of the previously available fibrin sealant Quixil? (in the EU) or Crosseal? (in the US). Evicel? differs from Quixil?/Crosseal? in that its fibrinogen component does not contain the antifibrinolytic agent tranexamic acid, which is potentially neurotoxic, resulting in Quixil?/Crosseal? being contraindicated for use in neurosurgery. The removal of tranexamic acid did not affect the haemostatic efficacy or longevity of Evicel? fibrin clots and allowed the sealant to be granted an expanded indication. Evicel? and Quixil?/Crosseal? are easy to use and, since they do not contain synthetic or bovine aprotinin, have a reduced potential for hypersensitivity reactions. This article reviews the pharmacological properties, clinical efficacy and tolerability of Evicel? and its previous formulation as supportive treatment for haemostasis in surgery. In clinical studies, Evicel? and Quixil?/Crosseal? were generally well tolerated and effective haemostatic agents for adjunctive use in various types of surgeries when conventional methods were impractical or ineffective in controlling bleeding. Two pivotal, randomized studies showed that Evicel? was significantly more effective than manual compression in patients undergoing vascular surgery, and significantly more effective than Surgicel? in patients undergoing retroperitoneal or intra-abdominal surgery, as assessed by the proportion of patients achieving haemostasis. In another similarly designed pivotal study in patients undergoing liver resection, Crosseal? was significantly more effective than standard haemostatic agents (e.g. Surgicel?), as assessed by the mean time to haemostasis. The incidences of treatment-emergent adverse events in these studies were generally similar between the Evicel? or Crosseal? groups and the comparator groups. Quixil? was also generally well tolerated and an effective haemostatic agent in endonasal surgeries, and tonsillectomies and/or adenoidectomies, with some benefit of treatment with Evicel? or Quixil? also observed in orthopaedic surgeries. Although additional comparative studies with other haemostatic agents would help to definitively position Evicel? with respect to these agents, current evidence suggests that Evicel? is useful in surgeries for improving haemostasis where standard surgical techniques are insufficient.     

Pharmacological strategies to decrease transfusion requirements in patients undergoing surgery

Surgical procedures are inevitably associated with bleeding. The amount of blood loss may vary widely between different surgical procedures and depends on surgical as well as non-surgical factors. Whereas adequate surgical haemostasis may suffice in most patients, pro-haemostatic pharmacological agents may be of additional benefit in patients with (diffuse) surgical bleeding or in patients with a specific underlying haemostatic defect. In general, surgical haemostasis and pharmacological therapies can be complementary in controlling blood loss. The use of pharmacological therapies to reduce blood loss and blood transfusions in surgery has historically been restricted to a few drugs. Antifibrinolytic agents (aprotinin, tranexamic acid and aminocaproic acid) have the best evidence supporting their use, especially in cardiac surgery, liver transplantation and some orthopaedic surgical procedures. Meta-analyses of randomised, controlled trials in cardiac patients have suggested a slight benefit of aprotinin, compared with the other antifibrinolytics. Desmopressin is the treatment of choice in patients with mild haemophilia A and von Willebrand disease. It has also been shown to be effective in patients undergoing cardiac surgery who received aspirin up to the time of operation. However, overall evidence does not support a beneficial effect of desmopressin in patients without pre-existing coagulopathy undergoing elective surgical procedures. Topical agents, such as fibrin sealants have been successfully used in a variety of surgical procedures. However, only very few controlled clinical trials have been performed and scientific evidence supporting their use is still limited. Novel drugs, like recombinant factor VIIa (eptacog alfa), are currently under clinical investigation. Recombinant factor VIIa has been introduced for the treatment of haemophilia patients with inhibitors, either in surgical or non-surgical situations. Preliminary data indicate that it may also be effective in surgical patients without pre-existing coagulation abnormalities. More clinical trials are warranted before definitive conclusions can be drawn about the safety and the exact role of this new drug in surgical patients. Only adequately powered and properly designed randomised, clinical trials will allow us to define the most effective and the safest pharmacological therapies for reducing blood loss and transfusion requirements in surgical patients. Future trials should also consider cost-effectiveness because of considerable differences in the costs of the available pro-haemostatic pharmacological agents.     

Fibrin sealant: a review of its use in surgery and endoscopy

Fibrin sealant (fibrin adhesive; fibrin glue; Beriplast P1) is a haemostatic and wound support product consisting of the blood coagulation factors fibrinogen, factor XIII and thrombin, the antifibrinolytic agent aprotinin and calcium chloride. Fibrin sealant has been used to good effect in a wide variety of surgical and endoscopic procedures. Suture support was provided in series of patients with oesophageal, gastric, colonic or rectal anastomoses, and fibrin sealant was as effective in haemostasis as microcrystalline collagen powder in hepatic surgery. It did not reduce postoperative peritoneal drainage after elective cholecystectomy, however. A 41% reduction (p<0.02) in incidence of air leakage was achieved when fibrin sealant was added to sutures in patients undergoing pulmonary resection in a randomised single-blind study. A high rate of complete remission of malignant pleural effusion has been reported after intrapleural instillation of fibrin sealant, and successful sealing of CSF leaks after trauma or surgery has also been achieved. Attenuation of prolonged or excessive haemorrhage after dental extraction has been achieved in patients on anticoagulant therapy or with haemorrhagic disorders who received fibrin sealant with packing and suturing. Repeated endoscopic injection of fibrin sealant was superior to single injection sclerotherapy with polidocanol 1% in a randomised study in 805 patients with bleeding peptic ulcers. Other data suggest that endoscopic injection of fibrin sealant is associated with lower recurrence of bleeding and need for emergency surgery than thrombin with adrenaline (epinephrine) or hypertonic saline with adrenaline. Similar haemostatic efficacy to laser photocoagulation or sclerotherapy was reported in a retrospective comparison. A statistically significant reduction relative to suturing in the incidence of wound dehiscence was reported after the use of fibrin sealant in cataract surgery, and benefit of the sealant has also been noted in patients receiving skin grafts and in those undergoing transurethral resection of the prostate gland. CONCLUSIONS: Although comparative studies would assist in the clarification of the place of the product discussed with respect to other haemostatic or wound support techniques and to other fibrin sealants, the formulation reviewed here has been shown overall to be effective and well tolerated in a variety of haemostatic and wound healing support roles in numerous types of surgery. Fibrin sealant has also been shown to be useful when administered endoscopically, with superiority over sclerotherapy being shown after repeated application in patients with peptic ulceration. Fibrin sealant can therefore be considered useful in a number of surgical and endoscopic settings.     

Efficacy of a haemostatic matrix for the management of bleeding in patients undergoing liver resection: results from 237 cases

ABSTRACT

Background: The haemostatic matrix (FloSeal) is a topical agent that provides effective haemostasis in a range of surgical applications. We evaluated this sealant for intra-operative haemostatic effectiveness in an observational series of patients undergoing surgery for the resection of primary and metastatic liver tumours.

Methods: A haemostatic matrix was applied directly to areas of bleeding. The severity of bleeding before and after application was graded on a 5-point scale (0 = no bleeding, 1 = oozing, 2 = moderate blood flow, 3 = heavy blood flow, 4 = spurting blood). The time to complete haemostasis was also recorded.

Results: 105 women (age 61 ± 9 years) and 132 men (age 61 ± 12 years) were included in this study. One hundred and seventeen patients (49.36%) had pre-operative coagulopathy resulting from co-existent cirrhosis (67 Child-Pugh Class A; 50 Child-Pugh Class B). Prior to administration of a haemostatic matrix, 93 bleeding sites (24.8%) had a bleeding severity score of 2, 269 bleeding sites (71.7%) had a score of 3 and 13 bleeding sites (3.5%) had a score of 4. Following administration of the haemostatic matrix, bleeding stopped completely (score of 0) at 367 (97.9%) of the 375 sites and was reduced to a score of 1 at the remaining 8 sites (2.1%), of which only 2 were in patients with coagulopathy. The mean time to achieve haemostasis in the overall population was 2.9 ± 1?min; this was significantly increased in patients with coagulopathy versus non-coagulopathic patients (4 ± 1 vs. 2 ± 1?min, p < 0.001).

Conclusions: In this prospective, uncontrolled study of 237 consecutive patients undergoing major hepatic surgery to remove primary or metastatic tumours, application of a haemostatic matrix provided rapid and effective intra-operative control of mild to severe bleeding from the liver edge, even in patients with prolonged bleeding times resulting from cirrhosis. This preliminary evidence warrants a randomised, controlled clinical trial with a larger sample size.     

Haemostatically active proteins in snake venoms

Snake venom proteins that affect the haemostatic system can cause (a) lowering of blood coagulability, (b) damage to blood vessels, resulting in bleeding, (c) secondary effects of bleeding, e.g. hypovolaemic shock and organ damage, and (d) thrombosis. These proteins may, or may not, be enzymes. We review the data on the most relevant haemostatically active proteinases, phospholipases A₂, l-amino acid oxidases and 5′-nucleotidases from snake venoms. We also survey the non-enzymatic effectors of haemostasis from snake venoms - disintegrins, C-type lectins and three-finger toxins. Medical applications have already been found for some of these snake venom proteins. We describe those that have already been approved as drugs to treat haemostatic disorders or are being used to diagnose such health problems. No clinical applications, however, currently exist for the majority of snake venom proteins acting on haemostasis. We conclude with the most promising potential uses in this respect.     

Practical applications of snake venom toxins in haemostasis

Snake venom toxins affecting haemostasis have facilitated extensively the routine assays of haemostatic parameters in the coagulation laboratory. Snake venom thrombin-like enzymes (SVTLE) are used for fibrinogen/fibrinogen breakdown product assay and for the detection of fibrinogen dysfunction. SVTLE are not inhibited by heparin and can thus can be used for assaying antithrombin III and other haemostatic variables in heparin-containing samples. Snake venoms are a rich source of prothrombin activators and these are utilised in prothrombin assays, for studying dysprothrombinaemias and for preparing meizothrombin and non-enzymic forms of prothrombin. Russell's viper (Daboia russelli) venom (RVV) contains toxins which have been used to assay blood clotting factors V, VII, X, platelet factor 3 and, importantly, lupus anticoagulants (LA). Other prothrombin activators (from the taipan, Australian brown snake and saw-scaled viper) have now been used to assay LA. Protein C and activated protein C resistance can be measured by means of RVV and Protac^®, a fast acting inhibitor from Southern copperhead snake venom and von Willebrand factor can be studied with botrocetin^® from Bothrops jararaca venom. The disintegrins, a large family of Arg-Gly-Asp (RGD)-containing snake venom proteins, show potential for studying platelet glycoprotein receptors, notably, GPIIb/IIIa and Ib. Snake venom toxins affecting haemostasis are also used in the therapeutic setting: Ancrod (from the Malayan pit viper, Calloselasma rhodostoma), in particular, has been used as an anticoagulant to achieve ‘therapeutic defibrination’. Other snake venom proteins show promise in the treatment of a range of haemostatic disorders.     

Introduction to haemostasis from a pharmacodynamic perspective

Biochemical characterization of the haemostatic system has advanced significantly in the past decades. Sub-systems, such as coagulation, fibrinolysis, blood cells and platelets and the vessel wall have been studied by specialists, mostly separately and independently. The time has come to integrate the approaches, and, in particular, to develop tests to document the state of the whole system and to have available adequate pharmacodynamic tests to evaluate treatments. Many examples are available to show that traditional general methods of clotting and lysis do not provide the information that is desired. The present tendency is to use specific methods for specific factors or effects which are very limited in pharmacological information. There is also increasing awareness of the occurrence of rather broad interindividual variability in the haemostatic system. This suggests that individually tailored treatments are required. This is the more relevant since haemostasis is a balance and treatment should be positioned between efficacy and safety. The conclusion is reached that there is a need for integrated or global methods or sets of methods that reflect the complexity and individual status appropriately and allow the practitioner to judge the effects of interventions and their individual aspects.     

Octocog alfa, plasma/albumin-free method

Octocog alfa, plasma/albumin-free method (octocog alfa-PFM) is a recombinant, human, full length, coagulation factor VIII that has been produced without the addition of human- or animal-derived plasma proteins, thereby virtually eliminating the risk of transmission of blood-borne pathogens. Octocog alfa-PFM is structurally and functionally very similar to a previously marketed, albumin-containing formulation of the same recombinant factor VIII. The haemostatic efficacy of octocog alfa-PFM was rated excellent or good in the acute treatment of most breakthrough bleeding episodes in adolescents or adults with moderately severe or severe haemophilia A who were receiving prophylaxis with octocog alfa-PFM and who had been previously treated with factor VIII. Most bleeding episodes resolved after one or two infusions of octocog alfa-PFM. Efficacy was similar regardless of the cause or site of the bleeding episode. Similar excellent or good haemostatic efficacy was observed with octocog alfa-PFM in previously treated children aged <6 years with haemophilia A and during perioperative use in patients with haemophilia A undergoing surgical or invasive dental procedures. Octocog alfa-PFM was well tolerated during clinical development and in the 15-month post-marketing period. There were very few adverse events and serious events were rare. The risk for developing inhibitors (antibodies) to factor VIII was very low.     

Simultaneous determination of coagulation and fibrinolysis parameters for diagnostics of disseminated intravascular blood coagulation (DIC).

A diagnostic method is described for determining the parameters of the human blood plasma coagulation and fibrinolysis by turbidimetry. Diluted plasma with thrombin and streptokinase is mixed to initiate clot formation and subsequent clot dissolution. The resultant profile of absorbance versus time is analysed to determine six parameters: plasma coagulation time, the rate of coagulation, fibrinogen concentration, the rate of fibrinolysis, fibrin clot half-lysis and lysis time. The assay is precise, sensitive and requires 0.1 ml plasma. The method has a good correlation with generally accepted haemostatic tests and allowed us to recognize the stage of DIC syndrome for less than 10 minutes. This new approach was successfully applied for studying the haemostasis in patients with acute intestinal infection.     

Development of haemostatic decontaminants for the treatment of wounds contaminated with chemical warfare agents. 1: Evaluation of in vitro clotting efficacy in the presence of certain contaminants

The treatment of penetrating, haemorrhaging injuries sustained within a hazardous environment may be complicated by contamination with toxic chemicals. There are currently no specific medical countermeasures for such injuries. Haemostats with an absorbent mechanism of action have the potential to simultaneously stop bleeding and decontaminate wounds. However, a primary requirement of a ‘haemostatic decontaminant’ is the retention of clotting function in the presence of chemical contaminants. Thus, the aim of this study was to investigate the haemostatic efficacy of seven commercially available haemostats in the presence of toxic chemicals (soman, VX, sulphur mustard, petrol, aviation fuel and motor oil). Clot viscosity was assessed ex vivo using thrombelastography following treatment of pig blood with: (i) toxic chemical; (ii) haemostat; or (iii) haemostat in combination with toxic chemical. Several contaminants (VX, petrol and GD) were found to be pro‐haemostatic and none had an adverse effect on the rate with which the test products attained haemostasis. However, the total clot strength for blood treated with certain haemostats in the presence of sulphur mustard, soman and petrol was significantly decreased. Three test products failed to demonstrate haemostatic function in this ex vivo (thrombelastography) model; this was tentatively ascribed to the products achieving haemostasis through a tamponade mechanism of action, which can only be replicated using in vivo models. Overall, this study has identified a number of commercial products that may have potential as haemostatic decontaminants and warrant further investigation to establish their decontaminant efficacy. Copyright © 2014 John Wiley & Sons, Ltd.     

Study of haemostasis in depressive patients treated with fluoxetine

The object of this study was to investigate a possible pharmacological effect of fluoxetine on haemostatic function, with special attention on primary haemostasis, in order to explain haemorrhagic complications reported in some treated, depressed patients. The haemostatic function of depressive patients, who required fluoxetine therapy, was studied before and after 1 month of treatment with fluoxetine 20 or 40 mg daily. Exclusion criteria were: pregnancy, initial abnormal haemostatic function, history of coagulation abnormalities, treatment with drugs that interfere with haemostasis, and recent fluoxetine therapy. The following tests were performed: prothrombin time, partial thromboplastin time, thrombin time, plasma fibrinogen, platelet counts, bleeding time, platelet aggregation induced by ADP, epinephrine, ristocetin, collagen, arachidonic acid, and plasma determination of fluoxetine and norfluoxetine levels. Statistical analysis was performed by Wilcoxon paired sample, one-tailed test (alpha=0.05). Among 18 patients included, only eight completed the trial. The single statistically significant difference was a decreased velocity in platelet aggregation induced by epinephrine without increased bleeding time. The results failed to demonstrate any compromised haemostatic function after 20 mg daily fluoxetine therapy in patients with initial haemostatic function. However, the results suggest possible effects of fluoxetine on platelet adrenoreceptors.     

Haemostatic imbalance following carrageenan-induced rat paw oedema

Carrageenan-induced rat paw oedema is a widely used model to investigate the physiopathology of an acute local inflammation. Recently, much attention has been focused on the link between haemostasis and inflammation, and on the impact that inflammation might have on thrombotic events. It is known that the systemic response to inflammation is the "acute phase reaction" that represents a highly complex reaction of the organism to a variety of injuries, aimed to restore homeostasis; one important feature of the acute phase reaction is the hepatic synthesis of proteins involved in the coagulation cascade. Much attention has been focused on the role that systemic inflammation might have on thrombotic events, while there is not much information on the role played by an acute local inflammation on haemostasis, that can lead toward a pro-thrombotic state. The present study was conducted to evaluate the haemostatic balance in the early and the late phase of carrageenan-induced rat paw oedema; i.e. at 3 h, when paw inflammation is maximally expressed, and 24 h following carrageenan injection, when there is an almost complete absence of local inflammatory symptoms. We found that in inflamed animals, 24 h following oedema induction, there was an increase in plasma fibrinogen levels, antithrombin III activity and serum interleukin-6 levels, concomitant to a shortened prothrombin time and to an increased platelet responsiveness to ADP. Furthermore, in inflamed tissues at 3 h there was an increase in antithrombin III proteic expression. Our results demonstrate that a haemostatic imbalance occurs following carrageenan-induced rat paw oedema.     

Fatty acids and atherosclerotic risk

Most research concerning the effects of dietary fatty acids on atherosclerotic risk has focused on their effects on lipid and lipoprotein metabolism. However, it is known that fatty acids also influence a number of other relevant mechanisms involved in atherosclerosis such as lipid peroxidation, inflammation and haemostasis. The most favourable distribution of cholesterol over the various lipoproteins is achieved when saturated and trans fatty acids are replaced by a mixture of cis-unsaturated fatty acids. Furthermore, fatty acids from fish oil lower triacylglycerol concentrations. Effects on other atherosclerotic risk markers are less evident. Monounsaturated fatty acids maybe preferable above other fatty acids with respect to low-density lipoprotein oxidation as measured by indirect in vitro assays. The relevance of these assays for the in vivo situation is, however, limited. With respect to inflammation, mainly the effects of n-3 polyunsaturated fatty acids from fish oil have been studied, but results were inconsistent. Also results from studies evaluating the effects of fatty acids on haemostatic risk markers were inconsistent, which may be partly related to the use of different analytical methods. The most consistent finding however is the potential beneficial effect of moderate intakes of fish oil on platelet aggregation. Furthermore, reducing total fat intake rather than changing the fatty acid composition of the diet may beneficially affect the coagulation system. In conclusion, while beneficial effects on atherosclerotic risk are mainly ascribed to cis-unsaturated fatty acids, it remains debateable whether trans and saturated fatty acids in the diet have to be replaced by cis-unsaturated fatty acids or by carbohydrates. To answer this question adequately more validated methods are needed that reflect in vivo lipid peroxidation, inflammation and haemostasis.     

Fibrin sealant in wound repair: a systematic survey of the literature

Fibrin sealants have recently been approved for clinical use in the US by the FDA and have been available for clinical use in Europe for years. The indication for use in the US is haemostasis. Nevertheless, both commercial and non-commercial fibrin sealant preparations are also for wound healing and for prevention of abdominal adhesions in the US and Europe. To the non-cognoscenti of fibrin sealants, their use to promote wound repair and to prevent abdominal adhesions appears contradictory since an agent that promotes connective tissue repair might be expected to promote abdominal adhesion rather than prevent them. In this systematic survey of the animal and clinical data evidence is presented that supports both off-label uses. However there is much inconsistency in the data secondary to the use of various fibrin sealant preparations, different animal models and clinical situations and different application techniques. It is clear from this survey that standard preparation and application of fibrin sealant for a particular surgical setting are needed to resolve the many apparent discrepancies in the literature. A corollary to this is the likelihood that different fibrin sealant preparations may be preferred for different clinical situations.     

Fibrin sealant in wound repair: a systematic survey of the literature

Fibrin sealants have recently been approved for clinical use in the US by the FDA and have been available for clinical use in Europe for years. The indication for use in the US is haemostasis. Nevertheless, both commercial and non-commercial fibrin sealant preparations are also for wound healing and for prevention of abdominal adhesions in the US and Europe. To the non-cognoscenti of fibrin sealants, their use to promote wound repair and to prevent abdominal adhesions appears contradictory since an agent that promotes connective tissue repair might be expected to promote abdominal adhesion rather than prevent them. In this systematic survey of the animal and clinical data evidence is presented that supports both off-label uses. However there is much inconsistency in the data secondary to the use of various fibrin sealant preparations, different animal models and clinical situations and different application techniques. It is clear from this survey that standard preparation and application of fibrin sealant for a particular surgical setting are needed to resolve the many apparent discrepancies in the literature. A corollary to this is the likelihood that different fibrin sealant preparations may be preferred for different clinical situations.     

Screening haemostasis--looking for global assays: the Overall Haemostasis Potential (OHP) method--a possible tool for laboratory investigation of global haemostasis in both hypo- and hypercoagulable conditions

A broad spectrum of global haemostatic assays has recently been developed and modified in an attempt to overcome the drawbacks of classical screening tests used for evaluation of coagulation and fibrinolysis. The Overall Haemostasis Potential (OHP) assay is one of such assays. The assay is based on repeated spectrophotometric registration of fibrin-aggregation in citrated plasma, to which small amounts of exogenous thrombin, tissue type plasminogen activator and calcium chloride have been added. The area under the fibrin aggregation curve which then develops is calculated and is the laboratory parameter used for OHP determination. The Overall Coagulation Potential (OCP) and Overall Fibrinolytic Potential (OFP) are supplementary parameters of OHP, providing details of underlying changes in coagulation and/or fibrinolysis. The sensitivity of the assay for detecting hypercoagulation in normal pregnancy, in preeclampsia, some thrombophilias, coronary heart disease, diabetes, stroke and vascular surgery has been evaluated. Since the assay can monitor haemostasis balance in the sample, it may serve as a laboratory tool to determine hypocoagulation, especially in patients with haemophilia A or B. Preliminary findings also indicate that the OHP assay may be useful in the monitoring of anticoagulant treatments. Larger controlled clinical studies are, however, mandatory before a definite conclusion about the usefulness of the method can be drawn.     

Review article: acid suppression in non-variceal acute upper gastrointestinal bleeding

Despite a decreased incidence of ulcer disease and improvements in the management of acute upper gastrointestinal (GI) bleeding, mortality remains at about 6-7%. Although endoscopic haemostatic therapy has been demonstrated to be the mainstay of management, the search continues for less invasive medical modalities that might also improve patient outcome. In vitro data have indicated the important role of acid in impairing haemostasis and causing clot digestion. Therefore, theoretically, maintenance of a high intragastric pH (above 6.0) during management of upper GI bleeding is warranted. Until recently, available agents did not permit such a sustained elevation in gastric pH. Early studies with H2-receptor antagonists have not demonstrated significant improvements in important patient outcomes, such as rebleeding, surgery or mortality. With the availability of intravenous formulations of proton pump inhibitors, it is now possible to aim at maintaining gastric pH above 6.0 for 24 h per day. Recent clinical trial data would appear to support the use of proton pump inhibitors to decrease the rate of rebleeding and the need for surgery. This paper provides a review of non-variceal acute GI bleeding, with special reference to the role of proton pump inhibitors in this clinical setting.     

The performance of a novel ball‐tipped Flush knife for endoscopic submucosal dissection: a case–control study

Aliment Pharmacol Ther 2010; 32: 908–915

Summary

Background Endoscopic submucosal dissection (ESD) using short needle knives is safe and effective, but bleeding is a problem due to low haemostatic capability. Aim To assess the performance of a novel ball‐tipped needle knife (Flush knife‐BT) for ESD with particular emphasis on haemostasis. Methods A case–control study to compare the performance for ESD of 30 pairs of consecutive early gastrointestinal lesions (oesophagus: 12, stomach: 32, colorectum: 16) with standard Flush knife (F) vs. Flush knife‐BT (BT). Primary outcome was efficacy of intraprocedure haemostasis. Secondary outcomes included procedure time, procedure speed (dividing procedure time into the area of resected specimen), en bloc resection rate and recurrence rate. Results Median intraoperative bleeding points and bleeding points requiring haemostatic forceps were smaller in the BT group than in the F group (4 vs. 8, P < 0.0001, 0 vs. 3, P < 0.0001). There was no difference between groups for procedure time; however, procedure speed was shorter in the BT group (P = 0.0078). En bloc and en bloc R0 resection rates were 100%, with no perforation or post‐operative bleeding. No recurrence was observed in either group at follow‐up 1 year postprocedure. Conclusions Ball‐tipped Flush knife (Flush knife‐BT) appears to improve haemostatic efficacy and dissection speed compared with standard Flush knife.     

Platelet substitutes and novel platelet products

Despite many advances in the safety, processing and storage of conventional 22 degrees C liquid-stored allogeneic platelet concentrates, there are still significant drawbacks to standard platelet concentrates used in transfusions for patients with thrombocytopenia. Efforts to overcome these shortcomings have been undertaken in both academic and commercial settings, resulting in an array of novel platelet products and substitutes that are currently at various stages of development. This review summarises the recent developments in lyophilised platelets, infusible platelet membranes (IPM), red cells bearing arginine-glycine-aspartic acid (RGD) ligands, fibrinogen-coated albumin microcapsules and liposome-based agents as putative alternatives to conventional transfusions involving allogeneic platelet concentrates. These various products are designed to replace the use of allogeneic donor platelets with modified or artificial platelets, to augment the function of existing platelets and/or provide a procoagulant material capable of achieving primary haemostasis in patients with thrombocytopenia. Preclinical studies have been encouraging for several of these platelet substitutes and novel platelet products, however, to date, only a few of these products have entered human trials. With the ongoing development of these diverse products, properties necessary for haemostatic effectiveness will become apparent. Safety and efficacy, however, must be demonstrated in preclinical and Phase I - III clinical trials, before these novel agents can be used clinically for patients with thrombocytopenia.     

Platelet substitutes and novel platelet products

Despite many advances in the safety, processing and storage of conventional 22ºC liquid-stored allogeneic platelet concentrates, there are still significant drawbacks to standard platelet concentrates used in transfusions for patients with thrombocytopenia. Efforts to overcome these shortcomings have been undertaken in both academic and commercial settings, resulting in an array of novel platelet products and substitutes that are currently at various stages of development. This review summarises the recent developments in lyophilised platelets, infusible platelet membranes (IPM), red cells bearing arginine-glycine-aspartic acid (RGD) ligands, fibrinogen-coated albumin microcapsules and liposome-based agents as putative alternatives to conventional transfusions involving allogeneic platelet concentrates. These various products are designed to replace the use of allogeneic donor platelets with modified or artificial platelets, to augment the function of existing platelets and/or provide a procoagulant material capable of achieving primary haemostasis in patients with thrombocytopenia. Preclinical studies have been encouraging for several of these platelet substitutes and novel platelet products, however, to date, only a few of these products have entered human trials. With the ongoing development of these diverse products, properties necessary for haemostatic effectiveness will become apparent. Safety and efficacy, however, must be demonstrated in preclinical and Phase I - III clinical trials, before these novel agents can be used clinically for patients with thrombocytopenia.