Gregory Yh Lip

Omar M Durrani

Vanessa Roldan

Peck Lin Lip

Francisco Marin

Tristan Q Reuser

Professor Gyh Lip

PERI-OPERATIVE MANAGEMENT OF OPHTHALMIC PATIENTS TAKING ANTI-THROMBOTIC THERAPY

Keywords: aspirin, warfarin, anticoagulation, ophthalmic surgery

Background. Increasing number of patients presenting for ophthalmic surgery are using oral anti-coagulant and anti-platelet therapy. The current practice of discontinuing these drugs pre-operatively due to a presumed increased risk of bleeding may not be evidencebased and could pose a significant risk to the patient's health.

Objective.

To provide an evidence-based review on the peri-operative management of ophthalmic patients that are taking anti-thrombotic therapy. In addition, we briefly discuss the underlying conditions that necessitate the use of these drugs, as well as management of the operative field in anti-coagulated patients.

Methods. A semi-systematic review of literature was performed. The databases searched included MEDLINE, EMBASE, database of abstracts of reviews of effects (DARE),

Cochrane controlled trial register and Cochrane systematic reviews. In addition, the bibliographies of the included papers were also scanned for evidence.

Results

The published data suggests that aspirin did not appear to increase the risk of serious post-operative bleeding in any type of ophthalmic surgery. Topical, sub-tenon, peri-bulbar and retrobulbar anesthesia appear to be safe in patients on anti-thrombotic (warfarin and aspirin) therapy. Warfarin does not increase the risk of significant bleeding in most types of ophthalmic surgery when the INR was within the therapeutic range.

Conclusion.

Current evidence supports the continued use of aspirin and with some exceptions, warfarin in the peri-operative period. The risk of thrombosis-related complications on disruption of anticoagulation may be higher than the risk of significant bleeding by continuing its use for most types of ophthalmic surgery.

Introduction

Increasing number of patients presenting for ophthalmic surgery are using oral anticoagulant and anti-platelet therapy. [START_REF] Katz | Risks and benefits of anticoagulant and antiplatelet medication use before cataract surgery[END_REF] Common medical conditions, such as atrial fibrillation and valvular heart disease, require the use of anticoagulants (e.g. warfarin), whilst antiplatelet therapy is used in high risk populations to reduce vascular events. [START_REF] Kitchin | Longitudinal survey of ischaemic heart disease in a randomly selected sample of the older population[END_REF][START_REF]Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. EAFT (European Atrial Fibrillation Trial) Study Group[END_REF] For example, there are one million people in America who are receiving warfarin, making it the 46 th most commonly prescribed drug in USA in 1993. [START_REF] Fihn | The risk for and severity of bleeding complications in elderly patients treated with warfarin. The National Consortium of Anticoagulation Clinics[END_REF] As patients over the age of 65 years are twice as likely to have some form of surgery as compared to those under that age the true importance of managing peri-operative antithrombotic therapy becomes clear. These drugs are routinely discontinued preoperatively due to a perceived increased risk of severe bleeding intra and postoperatively, a practice which is generally not based on published evidence and the potential risks to the patient may be poorly understood (Table 1). Nonetheless, the risk of peri-operative bleeding in patients on anti-coagulants is dependant on multiple factors including the patient's age, other systemic diseases (cancer), the type of surgery as well as the INR. [START_REF] Schulman | Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)[END_REF][START_REF] Palareti | Bleeding with anticoagulation therapy -who is at risk, and how best to identify such patients[END_REF][START_REF] Hughes | Guideline Development Group for the NICE national clinical guideline for management of atrial fibrillation in primary and secondary care. Risk factors for anticoagulation-related bleeding complications in patients with atrial fibrillation: a systematic review[END_REF] The underlying clinical state, the type of surgery and the phenomenon of rebound hypercoagulability on interruption of warfarin contributes to the risk of thrombosis-related complications.

The aim of this overview is to provide a semi-systematic review of the current published evidence on the peri-operative management of anti-coagulant and anti-platelet therapy.

In particular, we will review the risk of significant bleeding in patients on anti-coagulant than others. We will also assess the risks of thrombosis-related complications associated with short-term modification of these drugs and stratify the risk on the basis of underlying systemic disease. Management of the surgical field in ophthalmic patients on anti-coagulants will be summarized.

Methods used in undertaking this overview, as well as a brief overview of the indications for anti-thrombotic therapy [START_REF] Hughes | Guideline Development Group for the NICE national clinical guideline for management of atrial fibrillation in primary and secondary care. Risk factors for anticoagulation-related bleeding complications in patients with atrial fibrillation: a systematic review[END_REF][START_REF] Lagerstedt | Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis[END_REF][START_REF] Levine | Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis[END_REF][START_REF] Coon | Recurrence of venous thromboembolism[END_REF][START_REF]Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism[END_REF][START_REF] Lip | Atrial fibrillation and stroke prevention[END_REF][START_REF] Risk In Atrial Fibrillation | Independent predictors of stroke in patients with atrial fibrillation: a systematic review[END_REF][START_REF] Cannegieter | Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses[END_REF][START_REF] Stein | Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves[END_REF][START_REF] Bonow | ACC/AHA Guidelines for the Management of Patients With Valvular Heart Disease. Executive Summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients With Valvular Heart Disease)[END_REF][START_REF] Greaves | Guidelines on the investigation and management of the antiphospholipid syndrome[END_REF][START_REF] Khamashta | Management of antiphospholipid syndrome[END_REF][START_REF] Khamashta | Clinical study and follow-up of 100 patients with the antiphospholipid syndrome[END_REF] are provided as web-only supplementary material.

Altering anti-thrombotic therapy and the risk of thrombotic complications

The risks of thrombotic complications on one hand and bleeding on the other are dependent on multiple factors, including the type of anti-thrombotic therapy, the type and duration of surgery and rebound hypercoagulability that may be associated with stopping warfarin.

Aspirin users may be placed in two broad overlapping groups: those with significant cardiovascular risk factors where aspirin plays a significant cardioprotective and antithrombotic role, and those taking aspirin to keep the circulation "healthy". There is no published evidence to suggest that aspirin use in the latter group is beneficial. In the former group, in addition to the cardio-protective effect, aspirin reduces the risk of stroke by an average of 22% [START_REF] Kitchin | Longitudinal survey of ischaemic heart disease in a randomly selected sample of the older population[END_REF][START_REF] Ginsberg | Antiphospholipid antibodies and venous thromboembolism[END_REF] . Of note, current guidelines recommended dual antiplatelet therapy after coronary stenting especially with drug eluting stents, as early antiplatelet discontinuation may increase the risk of stent thrombosis The clinical relevance of rebound hypercoagulability is disputed by many authorities, though there is evidence to suggest that the risk of thromboembolism is increased on abrupt cessation of warfarin by a combination of this phenomenon and the prothrombotic effect of surgery. [START_REF] Grines | Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians[END_REF][START_REF] Palareti | Warfarin withdrawal. Pharmacokinetic-pharmacodynamic considerations and evidence for "rebound" hypercoagulability after stopping anticoagulants[END_REF] Laboratory studies show increased levels of prothrombin, fibrin and thrombin activation in the early period after abrupt cessation of warfarin. [START_REF] Palareti | Warfarin withdrawal. Pharmacokinetic-pharmacodynamic considerations and evidence for "rebound" hypercoagulability after stopping anticoagulants[END_REF][START_REF] Genewein | Rebound after cessation of oral anticoagulant therapy: the biochemical evidence[END_REF] Post-operative changes in haemostatic markers also suggest that surgery itself may increase the thrombophilic risk. [START_REF] Palareti | Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants--a prospective study[END_REF] Furthermore, high levels of a fibrin degradation product, fibrin D-dimer, may actually be predictive of the risk of postoperative thrombosis [START_REF] Kluft | The postoperative fibrinolytic shutdown: a rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma[END_REF][START_REF] Rowbotham | Measurement of crosslinked fibrin derivatives in patients undergoing abdominal surgery: use in the diagnosis of postoperative venous thrombosis[END_REF] .

An overview of studies examining the effect of altering antithrombotic therapy and the risk of thrombotic complications suggests a greater risk for patients with mitral valve disease, combined mitral and aortic prosthetic valves and atrial fibrillation. The exact thrombotic risk is dependent on multiple factors including the underlying systemic condition requiring anti-coagulation, duration of disruption and the use of bridging therapy (Table 3). [START_REF] Lip | Fibrin D-dimer: a useful clinical marker of thrombogenesis?[END_REF][START_REF] Carrel | Perioperative bleeding and thromboembolic risk during non-cardiac surgery in patients with mechanical prosthetic heart valves: an institutional review[END_REF][START_REF] Katholi | Living with prosthetic heart valves. Subsequent noncardiac operations and the risk of thromboembolism or hemorrhage[END_REF][START_REF] Katholi | The management of anticoagulation during noncardiac operations in patients with prosthetic heart valves. A prospective study[END_REF][START_REF] Tinmouth | Dalteparin as periprocedure anticoagulation for patients on warfarin and at high risk of thrombosis[END_REF] All these studies (either retrospective or prospective) have relatively small numbers.

Cataract surgery

Cataract surgery is one of the most commonly performed surgical procedures with over 200.000 procedures carried out in the United Kingdom in the last year. Most of the patients are elderly and a significant minority are on anticoagulants [START_REF] Katz | Risks and benefits of anticoagulant and antiplatelet medication use before cataract surgery[END_REF][START_REF] Dunn | Perioperative management of patients receiving oral anticoagulants: a systematic review[END_REF][START_REF] Douketis | The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)[END_REF] . The use of aspirin, clopidogrel and warfarin in the peri-operative period in patients undergoing cataract surgery does not appear to be associated with an increased risk of significant bleeding complications [START_REF] Katz | Risks and benefits of anticoagulant and antiplatelet medication use before cataract surgery[END_REF][START_REF] Dunn | Perioperative management of patients receiving oral anticoagulants: a systematic review[END_REF][START_REF] Douketis | The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)[END_REF][START_REF] Kallio | Haemorrhage and risk factors associated with retrobulbar/peribulbar block: a prospective study in 1383 patients[END_REF][START_REF] Carter | Phacoemulsification and lens implantation in patients treated with aspirin or warfarin[END_REF][START_REF] Shuler | Antiplatelet therapy and cataract surgery[END_REF][START_REF] Katz | Risks and benefits of anticoagulant and antiplatelet medication use before cataract surgery[END_REF] .

For example, one prospective study of 1383 patients investigated the bleeding risk of local anaesthetic infiltration in patients using aspirin, warfarin and other non steroidal anti-inflammatory drugs (NSAIDS) and undergoing a variety of ocular procedures. [START_REF] Kallio | Haemorrhage and risk factors associated with retrobulbar/peribulbar block: a prospective study in 1383 patients[END_REF] The overall risk of bleeding was found to be 4% (minor to moderate): there were no cases of retro-bulbar hemorrhage. Another large study investigating the risks of complications from the peri-operative use of anti-coagulant in 19,283 patients undergoing cataract surgery did not find an increase in the rates of haemorrhage in patients using warfarin or aspirin: 22.2% of patients were using aspirin while 4% were on warfarin preoperatively [START_REF] Dunn | Perioperative management of patients receiving oral anticoagulants: a systematic review[END_REF] . Aspirin was discontinued by 22% of users two weeks pre-operatively while 28.3% of warfarin users discontinued its use four days before surgery. Retrobulbar and/or peribulbar anesthesia was used in 73.9% while the rest had topical and/or subtenon blocks, and continued use of antithrombotic therapy (aspirin, warfarin) was recommended, as the rate of adverse bleeding events is not increased by their use.

Interestingly, the rate of thrombotic complications was much higher on interruption of anti-coagulants than the rate of bleeding complications on continued use in the study population. [START_REF] Katz | Risks and benefits of anticoagulant and antiplatelet medication use before cataract surgery[END_REF] Indeed, Gainey et al [START_REF] Gainey | Ocular surgery on patients receiving long-term warfarin therapy[END_REF] did not find a difference in the haemorrhage rate of patients irrespective of whether warfarin was continued or stopped before surgery. In patients who are undergoing cataract removal and are receiving vitamin K antagonists (VKAs), the ACCP8 guidelines recommend continuing warfarin around the time of the procedure [START_REF] Douketis | The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)[END_REF] . One study of patients undergoing cataract surgery found a greater incidence of subconjunctival hemorrhage in patients who were receiving either clopidogrel or warfarin compared to aspirin or no antithrombotic drugs, although there were no sight-threatening bleeding complications [START_REF] Kumar | Sub-Tenon's anesthesia with aspirin, warfarin, and clopidogrel[END_REF] .

Vitreoretinal surgery

Vitreoretinal surgery, though more invasive than cataract surgery, also appears to be safe in patients taking aspirin. For example, Narendran and Williamson [START_REF] Narendran | The effects of aspirin and warfarin therapy on haemorrhage in vitreoretinal surgery[END_REF] did not find an increased rate of bleeding complications in patients taking aspirin; however, only 7

patients in the study were taking warfarin, making it difficult to draw any firm conclusions from the higher bleeding rate in this sub-group. Fu at al. [START_REF] Fu | Anticoagulation with warfarin in vitreoretinal surgery[END_REF]

Glaucoma surgery

Trabeculectomy also appears to be safe in patients taking aspirin. In a retrospective study, Cobb et al. [START_REF] Cobb | The effect of aspirin and warfarin therapy in trabeculectomy[END_REF] reported that patients on aspirin had a postoperative hyphaema rate which was twofold compared to non-aspirin users, but there was no significant difference in surgical outcome when comparing intraocular pressures (IOP) at 2 years; however, In their small series, all 5 patients on warfarin developed clinically significant hyphaema, 2 of whom required surgical evacuation. Within 1 year, 4 cases needed antiglaucoma medication as IOP exceeded 21mmHg.

Lacrimal surgery

Lacrimal surgery can be associated with blood loss, sometimes significant [START_REF] Hannah | Open lacrimal surgery: a comparison of admission outcome and complications after planned day case or inpatient management[END_REF][START_REF] Hurwitz | The lacrimal system[END_REF] . In endonasal lacrimal surgery, visualisation is essential, and even a little blood loss will affect outcomes. Good hemostasis is therefore essential not only per-operatively, but also to prevent bleeding in the immediate postoperative period. Poor visibility during the operation correlates with poor outcomes.

Oculoplastic, Oro-facial & cutaneous surgery

Oro-facial and cutaneous surgery, including general plastic surgery and dermatologic procedures (eg. Moh's surgery) are broadly similar to oculoplastic and adnexal surgery, and evidence from these specialties are relevant to ophthalmologists.

Only one study investigating oculoplastic surgery in anti-coagulated patients was identified. [START_REF] Custer | Hemorrhagic complications of oculoplastic surgery[END_REF] The authors concluded that the incidence of serious haemorrhagic complications was low.

Cutaneous surgery generally appears safe in anti-coagulated patients. [START_REF] Otley | Continuation of medically necessary aspirin and warfarin during cutaneous surgery[END_REF] There is broad consensus that oral anticoagulants do not significantly increase the risk of bleeding and that stopping anticoagulant therapy does not offer significant benefits. [START_REF] Kargi | Complications of minor cutaneous surgery in patients under anticoagulant treatment[END_REF][START_REF] Shalom | Outcome of aspirin use during excision of cutaneous lesions[END_REF][START_REF] Ah-Weng | Preoperative monitoring of warfarin in cutaneous surgery[END_REF][START_REF] Alcalay | Cutaneous surgery in patients receiving warfarin therapy[END_REF] The rate of bleeding complications in anti-coagulated patients may be higher than those on aspirin but serious problems are uncommon. [START_REF] Billingsley | Intraoperative and postoperative bleeding problems in patients taking warfarin, aspirin, and nonsteroidal antiinflammatory agents. A prospective study[END_REF] Meticulous hemostasis with or without topical hemostatic agents like autologous fibrin glue or similar commercially available products and the use of pressure dressings postoperatively, further reduce this risk. One prospective study by Billingsley et al [START_REF] Billingsley | Intraoperative and postoperative bleeding problems in patients taking warfarin, aspirin, and nonsteroidal antiinflammatory agents. A prospective study[END_REF] found no difference between patients on warfarin, aspirin and controls. A retrospective review of 586 patients undergoing Moh's micrographic surgery reports a serious bleeding rate of 1.6% in patients taking warfarin and aspirin, although there was no difference between the treated (oral anticoagulants (OAC) continued) and untreated groups (OAC stopped). [START_REF] Otley | Complications of cutaneous surgery in patients who are taking warfarin, aspirin, or nonsteroidal antiinflammatory drugs[END_REF] Major thrombotic episodes including pulmonary embolism and thrombosis of prosthetic valve have also been reported when anticoagulant therapy was withheld prior to surgery. [START_REF] Alam | Serious Adverse Vascular Events Associated With Perioperative Interruption of Antiplatelet and Anticoagulant Therapy[END_REF] Finally, a recent meta-analysis of complications attributed to anticoagulation in patients following cutaneous surgery reported that patients taking warfarin were nearly seven times as likely to have a moderate-to-severe complication whereas patients taking aspirin were more than two-fold (but not statistically significant) to have a moderate-tosevere complication compared to controls [START_REF] Lewis | A meta-analysis of complications attributed to anticoagulation among patients following cutaneous surgery[END_REF] .

Oral and dental surgery

There is evidence that oral and dental surgery is safely carried out in chronically anticoagulated patients. A prospective randomised study comparing bleeding complications in patients continued on warfarin to those that had warfarin reduced or warfarin added found no statistically significant difference in the rate of bleeding complications. [START_REF] Souto | Oral surgery in anticoagulated patients without reducing the dose of oral anticoagulant: a prospective randomized study[END_REF] Another randomised controlled trial [START_REF] Evans | Can warfarin be continued during dental extraction? Results of a randomized controlled trial[END_REF] and aspirin should not be withdrawn as the benefits are low while the risks are high [START_REF] Carter | Current concepts of the management of dental extractions for patients taking warfarin[END_REF] Topical hemostatic agents like platelet rich fibrin gel could be used in patients at a higher risk of bleeding. [START_REF] Valle | Prevention of postoperative bleeding in anticoagulated patients undergoing oral surgery: use of platelet-rich plasma gel[END_REF] Five trials (a total of 553 patients) were included in a recent meta-analysis that evaluated the effect of continuing warfarin therapy on the bleeding risk of patients undergoing elective dental surgery [START_REF] Nematullah | Dental surgery for patients on anticoagulant therapy with warfarin: a systematic review and meta-analysis[END_REF] . Perioperative continuation of warfarin with patients' usual dose was not associated with an increased risk for clinically significant non major bleeding or an increased risk for minor bleeding compared with interrupting warfarin therapy (either partial or complete).

Modification of antithrombotic therapy

For most types of surgical procedures, the risks of interrupting anti-coagulation outweigh its benefits, but clinical needs may at times dictate disruption of warfarin or aspirin. If the INR is within the therapeutic range (2-3.5), discontinuing warfarin for three to four days will allow the INR to drop below 2.0. For those with INRs higher than the therapeutic range (ie >3.5), a longer period may be required. Consulting a cardiologist or a clinical haematologist is highly recommended in these cases.

A population of patients that deserves special consideration are patients on antiplatelet therapy related to coronary artery disease, since such patients are common, and often require chronic treatment. Indeed, a cardiologist should always be consulted where patients with coronary artery disease are on treatment with aspirin + clopidogrel (dual antiplatelet therapy) for an acute coronary syndrome or after recent stent implantation (whether drug eluting (DES) or bare metal stent (BMS) implantation.). In such patients, the risk of recurrent cardiac ischaemia or stent thrombosis is real, and non-urgent surgery (including ophthalmic procedures) should be delayed where possible, especially since the potential for bleeding with dual antiplatelet therapy may be as high as that seen with warfarin. The risk of thrombosis diminishes with time, and dual antiplatelet therapy is mandated for 4 weeks after elective BMS implantation, and for 6-12 months after DES implantation or an acute coronary syndrome. If urgent surgery is needed and cannot be delayed, and where the bleeding risk is significant, clopidogrel should be discontinued for 5 days, and restarted as soon as possible post-procedure [START_REF] Douketis | The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)[END_REF] . 3). [START_REF] Douketis | The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)[END_REF][START_REF] Spandorfer | Use of enoxaparin for the chronically anticoagulated patient before and after procedures[END_REF] Aspirin or clopidogrel is generally stopped 7 days prior to surgery. One prospective controlled trial suggests that stopping aspirin 48 hours before surgery is just as effective as seven days. 63

Urgent reversal of warfarin anticoagulation

In patients needing urgent surgery, two options are available to rapidly reduce the INR.

Vitamin K (phytonadione) is a fat soluble vitamin that is required for synthesis and biologic activity of coagulation factors II, VII, IX and X as well as Proteins C and S.

Warfarin inhibits the γ-carboxylation of the coagulation factors and limits their ability to bind calcium and form clots. A small dose (2.5-5 mg) of either oral or intravenous vitamin K will reverse the effects of warfarin within 24 to 36 hours. [START_REF] Heit | Perioperative management of the chronically anticoagulated patient[END_REF][START_REF] Crowther | Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial[END_REF][START_REF] Crowther | Vitamin K for the treatment of asymptomatic coagulopathy associated with oral anticoagulant therapy[END_REF] Intramuscular

Vitamin K injection should be avoided because of erratic absorption and the risk of hematoma formation. For life-threatening situations with a need for emergency surgery, guidelines recommend the use of fresh frozen plasma (FFP) to treat warfarin overdosage only where there is severe bleeding or prothrombin complex concentrates (PCCs) are unavailable.

Management of the operative field

While continuing anti-coagulants in the therapeutic range does not increase the risk of serious bleeding in most types of surgery, persistent bleeding or oozing from the operative site may be more than just an annoyance. In cutaneous, oculoplastic and lacrimal surgery, important tissue planes may be obscured and the risk of graft failure increased due to hematoma formation. Orbital, oto-laryangatologic and other "key-hole" procedures may become impossible because of poor view, and dangerous if associated with significant bleeding post-op. Simple steps such as meticulous surgical technique and a good understanding of local anatomy reduce surgical trauma. Also, hypotensive anesthesia is an excellent way of reducing intraoperative bleeding in most types of surgery but post operative bleeding is a risk as potential bleeding sites may not be identified. [START_REF] Ewards | Deliberate hypotension[END_REF][START_REF] Shepherd | Hypotensive anaesthesia and blood loss in orthognathic surgery[END_REF] Local infiltration with adrenaline is a tried and tested method of achieving local hemostasis and is especially useful in cutaneous, oculoplastic, and lacrimal surgery, and a dilution of 1:80,000 to 1:200,000 is effective when infiltrated about 10 minutes before surgery. [START_REF] Rasgon | Infiltration of epinephrine in tonsillectomy: a randomized, prospective, doubleblind study[END_REF] Radiofrequency cutting diathermy also reduces bleeding at the operative site by cauterizing the wound at the time of incision. [START_REF] Liboon | A comparison of mucosal incisions made by scalpel, CO2 laser, electrocautery, and constant-voltage electrocautery[END_REF] CO2 laser in the cutting mode works on a similar principal and can minimize bleeding. [START_REF] Goldbaum | The CO2 laser in oculoplastic surgery[END_REF]

Topical hemostatic agents

Fibrin Sealants enhance hemostasis at the operative site by duplicating the last phase of blood clot formation. A mixture of fibrinogen, thrombin, ionized calcium and factor XIII are applied locally. Thrombin converts fibrinogen in to fibrin and activates factor XIII.

This results in cross-linking of fibrin and increased clot strength. During the healing process, this material is gradually absorbed and may actually enhance wound healing. The preparations may be autologous, homologous and derived from pooled donors or bovine sources. To prepare the autologous gel, the patient needs to come to the hospital a few days before the procedure and give about 100-300ml of blood which is then processed to recover platelet rich fibrin glue and thrombin. [START_REF] Man | The use of autologous platelet-rich plasma (platelet gel) and autologous platelet-poor plasma (fibrin glue) in cosmetic surgery[END_REF] When this gel is applied to the operative field, the platelets come in contact with thrombin/calcium it results in their activation and coagulum formation. The platelets interdigitate with the fibrin web and develop an adhesive haemostatic layer. Platelet activation also releases highly active vasoconstrictors, including serotonin, thromboxane and platelet derived growth factor (PDGF). In addition to haemostasis, it also promotes wound healing and has "tissue glue" properties. [START_REF] Man | The use of autologous platelet-rich plasma (platelet gel) and autologous platelet-poor plasma (fibrin glue) in cosmetic surgery[END_REF][START_REF] Anitua | Autologous platelets as a source of proteins for healing and tissue regeneration[END_REF] Commercially available topical agents tend to be more effective as they contain much higher concentrations of clotting factors. [START_REF] Laitakari | Autologous and homologous fibrinogen sealants: adhesive strength[END_REF] The homologous products are screened for all currently known infectious agents but concerns remain. Bovine products like FlowSeal Matrix™ are another alternative. They are derived from closed herds that are screened for all known infections including prion diseases but the possibility of (rare) allergic reactions must be kept in mind.

A systemic review of randomised controlled trials of fibrin sealants by Carless et al [START_REF] Carless | Systematic review of the use of fibrin sealant to minimize perioperative allogeneic blood transfusion[END_REF] suggests that these agents reduce the rate of blood loss as well as reducing the need for transfusion. A multi-centre study comparing the efficacy of fibrin sealant with conventional topical haemostatic agents in emergency re-sternotomy and redo cardiac surgery found these agents to control bleeding within five minutes of application in 92.6% of patients compared to 12.4% in the conventional group. haemostatic agent, which is effective in stopping bleeding following endonasal surgery in an average of 2.5 minutes. [START_REF] Baumann | Hemostasis in endoscopic sinus surgery using a specific gelatin-thrombin based agent (FloSeal)[END_REF] A recent randomised controlled trial found it to be safe and effective in controlling post-operative bleeding following adenoid surgery in children. [START_REF] Mathiasen | Prospective, randomized, controlled clinical trial of a novel matrix hemostatic sealant in children undergoing adenoidectomy[END_REF] It does not appear to alter wound healing or flap survival in clinical studies but delayed mucosal healing and increased scarring was reported in one animal study. [START_REF] Jorgensen | The effect of 2 sealants (FloSeal and Tisseel) on fasciocutaneous flap revascularization[END_REF][START_REF] Maccabee | Effects of topically applied biomaterials on paranasal sinus mucosal healing[END_REF] Though there is no published evidence of the use of these topical products in orbital surgery, a recent study of trans-sphenoidal surgery found Flowseal to be effective in controlling severe bleeding where standard methods had failed. [START_REF] Ellegala | Use of FloSeal hemostatic sealant in transsphenoidal pituitary surgery: technical note[END_REF] Tisseal™, another topical agent is effective as hemostatic agent and tissue glue. [START_REF] Vogel | Surgical tissue adhesives in facial plastic and reconstructive surgery[END_REF] One of the major benefits of this product is the ability to vary the clotting rate by changing the dilution of the thrombin in the preparation.

Haemostatic sponges have been around for a long time and are used either alone or after soaking them in thrombin. [START_REF] Schonauer | The use of local agents: bone wax, gelatin, collagen, oxidized cellulose[END_REF] They work primarily by activating platelets and providing scaffolding for clot formation. [START_REF] Weaver | Gelatin-thrombin-based hemostatic sealant for intraoperative bleeding in vascular surgery[END_REF] Bone wax is a useful and cheap alternative for controlling moderate bleeding from bone. [START_REF] Schonauer | The use of local agents: bone wax, gelatin, collagen, oxidized cellulose[END_REF]

Conclusions

Even with the limited quality and quantity of evidence we are able to draw certain conclusions from the available data (Table 4). Figure 1 provides an algorithm for management of warfarinized patients undergoing ophthalmic surgery. While aspirin does not appear to be associated with an increased risk of significant bleeding in patients undergoing any type of ophthalmic surgery or infiltration of local anesthesia, no evidence of excessive thromboembolism on its discontinuation was identified. In procedures where oozing at the operative site may be detrimental to surgical outcome, aspirin may be discontinued in the peri-operative period in patients without significant cardio-vascular risk factors. The risk of significant bleeding in patients using warfarin and undergoing ophthalmic surgery appears to be relatively low when the INR is within the therapeutic range, whilst the probability of thromboembolism on its interruption appears to be much higher. Peri-operative modification of warfarin needs to be done cautiously and in close discussion with a cardiologist and/or clinical haematologist. Reducing the warfarin dose pre-operatively to bring down the INR to the lower limit of the therapeutic range is a safer alternative to disrupting it and exposing the patient to a risk of thromboembolism. There is also insufficient evidence to make precise recommendations about the newer anti-platelet drugs like clopidogrel and prasugrel. Evidence based recommendations for peri-operative management of warfarin and aspirin.

F

Aspirin or warfarin should not be discontinued prior to periocular infiltration of local anesthetic (sub-tenon, peri-bulbar or retro-bulbar).

In the presence of vasculopathic risk factors, aspirin should not be stopped prior to any type of ophthalmic surgery.

Cataract surgery can be safely carried out in patients taking aspirin or warfarin.

*With the exception of vitreo-retinal surgery, warfarin should be continued in patients undergoing ophthalmic surgery as the risk of thrombophilia is higher than the risk of significant bleeding.

Peri-operative modification of anti-coagulants should only be carried out after advice from a cardiologist/ clinical hematologist.

#In moderate to high risk patients, rather than stopping warfarin pre-operatively, its dose should be modified to reduce the INR to the lower end of the therapeutic range.

  platelet therapy and determine what types of ophthalmic procedures are safer

  reported 25 patients on warfarin undergoing vitreoretinal surgery, where the only reported complication was of one patient undergoing scleral buckling and external drainage of subretinal fluid where intraoperative subretinal haemorrhage was associated with the drainage procedure. The preoperative INR in this case was 2.7. Another retrospective study identified 54 patients who underwent 57 vitreoretinal surgical procedures while on warfarin anticoagulation therapy with an therapeutic INR 43 . There were no intraoperative hemorrhagic complications and only 4 postoperative haemorrhages, all of them resolved spontaneously.

  had serious haemorrhagic complications (INR ranged from 1.5 to 4.5).

  of 109 patients, comparing the discontinuation of warfarin two days pre-operatively with continued anti-coagulation did not find a the rate of post-operative bleeding, whereby the incidence of bleeding was 26% in the intervention group compared to 14% in the control group. Thus, for the management of anti-coagulated patients undergoing dental extraction, warfarin

A*

  No evidence found regarding glaucoma filtration surgery # Therapeutic INR range: 2-3.5

  [START_REF] Grines | Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians[END_REF]

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7 Antithrombotic therapy use, surgery & the risk of bleeding complications

	A recent systematic review by Dunne and Turpie 33 identified 31 studies relating to long-
	term oral anti-coagulants and surgery, and reported that the quality of evidence was
	generally poor. They concluded that most patients can undergo cutaneous, dental,
	ophthalmic surgery, arthrocentesis, and upper gastrointestinal endoscopy without
	alteration to oral anticoagulants. For other invasive surgery, they recommend withholding F oral anticoagulants and the use of heparin as bridging therapy 32,33 . The perioperative o r management of antithrombotic therapy has been the subject of an American College of
	P Chest Physicians Evidence-Based Clinical Practice Guideline (8th Edition;
	e ACCP8) 34 .and broadly recommends an approach based on thromboembolic risk. For e r example, in those at high risk for thromboembolism, ACCP8 recommends bridging
	anticoagulation with therapeutic-dose subcutaneous (SC) Low molecular weight heparin R e (LMWH) and IV unfractionated heparin (IV UFH) over no bridging during temporary
	interruption of warfarin therapy, whist in patients at moderate risk, bridging v i e anticoagulation with therapeutic-dose SC LMWH, therapeutic-dose IV UFH, or low-dose
	w SC LMWH is also recommended, over no bridging during temporary interruption of
	y complications describes 29 thrombotic events, including seven strokes in 1868 patients warfarin therapy. In patients with a mechanical heart valve or atrial fibrillation or venous thromboembolism at low risk for thromboembolism, low-dose SC LMWH or no bridging O n l is recommended.
	(1.6%; 95% CI, 1.0-2.1%) receiving oral anticoagulation and undergoing surgery or
	invasive procedures. 33

High quality prospective randomised studies are therefore needed to better define this risk. A meta-analysis of studies reporting thromboembolic

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  Elective surgery should be delayed if it has been less than a month since the thrombotic episode. Bridging therapy with low molecular weight heparin should only be instituted in patients at a moderate to high risk of thrombotic complications (table

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  [START_REF] Matras | Fibrin seal: the state of the art[END_REF]

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  [START_REF] Rousou | Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations. A multicenter study[END_REF]

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	Floseal Matrix™ is a bovine derived two component (gelatin matrix and thrombin)
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Table 1 . Potential problems in interrupting anti-coagulant therapy

 1 This overview highlights the heterogeneity of the data, with limited data from robust large randomised controlled trials, and dependence on case series. In summary, most types of ophthalmic surgery appear to be safe in anti-coagulated patients. When the disruption to warfarin is considered essential, it should be for the minimal possible time with low molecular weight heparin 'bridging; cover during the period of cessation as the risk of thrombophilia on interrupting oral anticoagulants appears to be higher than the risk of post-operative bleeding. The constant oozing of blood at the surgical field can also be proactively managed by a combination of local measures. The question of the best practice in the peri-operative management of chronically anti-coagulated patient is perhaps too important to ignore and well planned prospective studies are still needed.

	Limitations
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Table 3 . Systemic disease and the risk of thrombosis

 3

	Venous thrombosis > 3/12 ago	Low risk
	Non-valvular atrial fibrillation
	Bio-prosthetic valve	↓
	Aortic prosthetic valve	Moderate risk
	Atrial fibrillation
	Mitral valve	High risk
	Recurrent arterio/venous thrombophilia	↓
	Venous thrombosis < 1/12

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Table 4 .

 4

Table 2. Evidence included in this systematic review of antithrombotic therapy

ACKNOWLEDGEMENTS

We thank Fariha Shafi, Usman Mahmood and Anu Pherwani, for assistance with literature reviews.

Author