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83ured nerves and blood vessels. Intraoperative orstoperative anastomotic thrombosis necessitatesoperation and risks flap or replant failure. Sur-al intervention for thrombosis generally in-lves anastomotic revision or interposition veinafting. Despite these interventions vascularombosis is the leading cause of failure of mi-surgeries.15 With the incidence of flap failureorted to be as high as 10%, the primary preven-n of thrombosis is of critical interest to micro-scular surgeons.6Although anticoagulation has been part of re-nstructive surgery for 30 years, anticoagulationotocols vary widely among microsurgeons. Cur-tly 96% of reconstructive surgeons use antico-

ulants in free flap procedures.6,7 Numerous stud-evaluating prophylactic anticoagulation in

crosurgery report efficacy in animal models,wever, limited human data exist to support anynicians preferred method. It is unknownether the most efficacious protocol for human

summary of relevant basic science and clinical stud-ies in animal and human models. We hope that thisreview will assist surgeons with informed decisionmaking regarding the clinical use of anticoagulants inmicrosurgery.

Overview of Thrombosis in MicrosurgeryThe pathogenesis of venous thrombosis differs fromarterial thrombosis.8 Platelet aggregation is the un-derlying cause of arterial thrombosis whereas venousthrombosis is primarily the result of fibrin clotting.8Because venous thrombosis occurs more frequentlythan arterial thrombosis as the cause of free flapfailure, fibrin strand development is a more signifi-cant factor in microvascular occlusion than plateletaggregation.1,9,10

The risk for thromboses is highest (80%) duringthe first 2 postoperative days and decreases to 10%after postoperative day 3.2,9 In a study of the timingof pedicle thrombosis Ichinose et al3 found that 90%of purely arterial thrombi occur on postoperative day1 whereas 42% of purely venous thrombi occur afterAnticoagulatin Microsurge

Morad Askari, MD, Christine FisheSean Bidic, MD, W.

From the Division of Plastic and Reconstructive Surgeand the Division of Plastic and Reconstructive Surgery,

The advent of microsurgical tissue transfer inscope of reconstructive surgery. There are fewfor microsurgery, however, and anastomoticsurgical failure. No consensus exists on the idThis article reviews major pharmacologic mmechanism of action and study of efficacy of eof popular anticoagulation therapies. Finally,data and attempts to provide a glimpse of thetion research. (J Hand Surg 2006;31A:83684for Surgery of the Hand.)Key words: Microsurgery, anticoagulation, th

icrovascular techniques are key compo-nents of reconstructive hand surgery to6 The Journal of Hand SurgeryTherapy: A Review

S, Frederick G. Weniger, MD,ndrew Lee, MD

versity of Southern California, Los Angeles, CA;sity of Pittsburgh Medical Center, Pittsburgh, PA.

g replantation greatly has expanded thet innovations in anticoagulation therapiesmbosis remains an occasional cause ofticoagulation protocol for microsurgery.ities of anticoagulation, delineates thegent, and compares the risks and benefitsmines available human outcomesbasede direction of microsurgical anticoagula-pyright 2006 by the American Society

sis, flap, heparin.

crosurgical anticoagulation has yet to be identi-d or whether no singular effective method ex-

postoperative day 1. This risk pattern is attributed tothewh

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Askari et al / Anticoagulation in Microsurgery 837initially low flow volume through the pedicle,ich gradually increases in the postoperative period.Several surgical factors are associated with freep failure. The use of vein grafts in microsurgeryd the presence of chronic wounds at recipient sites

associated with greater postoperative vascularombosis and failure.4,11,12 Myocutaneous flapsd vein grafts are associated with increased throm-sis at the site of anastomosis and the free rectusdominis and transverse rectus abdominis muscleps are associated with increased patency comparedth other flaps.4Despite the variety of reconstructive techniquesd anticoagulation protocols used by microsur-ons, the reported failure rate among free flapsges from 4% to 10% and the reported failure rateong replants ranges from 15% to 30%.4,5,1315

any flaps are salvaged successfully with thrombo-ic treatment, indicating that the true rate of vascu-thrombosis in microsurgery is higher.16 Optimalphylactic anticoagulation therapy promises signif-nt reductions in morbidity.

tithrombotic Therapye use of prophylactic antithrombotic agents is thest common strategy for avoiding vascular throm-

sis after free flap surgery or vascular repair.1719early as 1978 Ketchman20 proposed that to in-

ase patency rates of microvascular repairs sur-ons need agents that (1) decrease platelet function, aspirin), (2) increase blood flow or decreaseod viscosity (eg, dextran), and (3) counteract theects of thrombin on platelets and fibrinogen (eg,parin). Today aspirin, dextran, and heparin are theinstay of treatment. The use of these agents re-ins complicated by the challenge of providingtimal antithrombotic prophylaxis while minimiz-

adverse effects.No consensus exists on the use of anticoagulationrapy after microsurgery. Many surgeons haveir own particular protocols for perioperative anti-

agulation that has been shaped by personal trialsd errors. The following sections review and sum-rize experimental studies and clinical experiencesorted in the current literature and provide an over-w and comparison of popular anticoagulationrapies.

parinparin, a polyglycosaminoglycan of varying lengths,s been used clinically for more than 50 years. It issurgeons to prevent both arterial and venousombosis.21 Heparin binds to antithrombin III andhances its antiprotease activity and accelerates itsachment to its substrate approximately 1,000-fold.a result the active forms of coagulation factors II

rombin), IX, X, XI, and XII are rendered inactived the clotting cascade is impaired.22 Through in-ition of thrombin generation heparin reduces the

tivation of coagulation factors V and VIII, recruit-nt of platelets, and formation of fibrin.23,24 The

tithrombotic effect of heparin is measured clini-lly by the increase in clotting time of blood and ispressed as prolonged activated partial thrombo-stin time (APTT). A 2-fold increase in PTT is

nsidered a therapeutic heparin level. In addition,ge doses of heparin result in vasodilation thatssibly is mediated by the release of nitric oxidem the endothelium.25 The vasodilative effect ofparin may reduce thrombosis further by increasing

rate of blood flow.Heparin prophylaxis is limited by an increased riskhemorrhage from the surgical site and formation

hematoma.26 Heparin therapy is associated with aater incidence of hematoma than aspirin or dex-n. In a retrospective study of lower-extremity re-nstruction using free flaps Pugh et al27 found a% rate of hematoma formation when heparin wased alone or in combination with other agents. Thisrrants discretion when administering unfraction-d heparin because increased tissue pressures

used by the formation of a hematoma at the site ofastomosis can compromise perfusion and encour-e thrombogenesis. In a recent retrospective review216 head and neck reconstruction patients given ambination of aspirin (325 mg every day) and sub-taneous heparin (5,000 U subcutaneously twice ay), Chien et al6 reported a free-flap survival rateuivalent to other anticoagulation regimens withoutincreased incidence of hematoma.

Another important side effect of heparin therapy isparin-induced thrombocytopenia (HIT).28,29 TypeIT is a rare (1%3%) immune-mediated conditiont results in a significant decrease in platelet count,00055,000) 5 to 10 days after the initiation of

parin therapy. It is treated only by cessation ofparin therapy. Type II HIT is a nonimmune con-ion with a smaller decrease in platelet count0,000), which occurs 1 to 2 days after the initia-

n of heparin therapy. Type II HIT usually im-ves spontaneously despite continuation of heparinrapy.30 When given as a bolus heparin can result

in hypotension in patients having cardiac surgery orheclures

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838 The Journal of Hand Surgery / Vol. 31A No. 5 MayJune 2006modialysis.3133 Disadvantages of heparin use in-de its low bioavailability and unpredictable dose-ponse relationship.34 Subcutaneous administrationpostoperative patients necessitates close monitor-

of fluctuating coagulation levels, which extendslength and increases the cost of the hospital

y.35The goal in heparin therapy is the efficient deliverya minimal therapeutic dose to the site of vascularastomosis. Maintaining low systemic heparin lev-minimizes the adverse effects of anticoagulation.oks et al36 reported no significant difference in thetective effect of intra-arterial and systemically

ministered intravenous heparin or dextran-40. Iner studies systemic heparin provided greater pro-tion against rethrombosis after the repair of aombosed anastomosis by vein graft repair than byple re-anastomosis alone (82% vs 69% patency,

pectively).37 Stockmans et al21 showed that hep-n, when administered systemically to a therapeuticel (a 2-fold increase in PTT), reduces the rate ofmary venous thrombosis by 60% whereas higherses result in close to a 100% reduction. Highersma levels of heparin result in better protection

ainst vascular thrombosis but increase the inci-nce of bleeding.21 In an attempt to deliver highal doses of heparin while maintaining low sys-ic levels, Hudson et al38 used an in situ venous

theter. The catheter was inserted proximal to thenous anastomosis in 83 free flaps to infuse 50mL at 10 mL/h for 48 hours and then the dose wasered over 5 days. They observed an increase ofal APTT whereas the systemic APTT remainedrmal. Ultimately they reported zero re-explora-ns or flap failures in comparison with the usualexploration rate of 12% in the absence of localnous catheter anticoagulation.Recently topical antithrombotic administration hasen suggested as an alternate approach to localticoagulation.39 Fu et al40 reported that topicalministration of high-concentration heparin (750 g/) results in 80% patency at the anastomosis sites

7 days in the rabbit model. Ten minutes of intra-erative irrigation with high-dose heparin directlythe anastomosis optimizes endothelial binding ofdrug and increases the local concentration of

parin.41,42 In a multicenter prospective humannical study, however, Khouri et al14 did not ob-ve a benefit to using intraluminal heparin irriga-n, regardless of concentration, in reducing postop-tive thrombosis. They did report a decrease in then with systemic heparin.Topical heparin irrigation may increase vessel pa-cy but the direct effect of the pressure can injurevessel. Yan et al43 reported that in the animal

del lactated Ringers solution pressures of 100Hg or greater injures the endothelial cells and

ernal elastic lamina, which may have a detrimentalect on microvascular anastomoses. Therefore irri-tion pressures less than 100 mm Hg minimizeuma to the delicate microvascular tissues and max-ize vessel patency.

w Molecular Weight Heparinsw molecular weight heparin (LMWH) is a deriv-ve of unfractionated heparin that is preparedough the deaminative hydrolysis of standard hep-n into short polysaccharide fragments. These mol-ules are known to have the same inhibitory effect

active factor X but have a weaker antithrombinctor II) activity. As a result LMWH is as effica-us as unfractionated heparin in preventing venousombosis with fewer adverse effects.44,45 Malmal34 observed that LMWH (dalteparin) thrombinibition is sufficient to prevent thrombosis and

es not cause a significant increase in bleeding. Bying a rat model of deep arterial injury, doses of 180kg LMWH or heparin caused a similar antithrom-tic effect (close to 3-fold increase in patency at 30nutes after surgery) but only the heparin group re-lted in a statistically significant increase in bleeding.The efficacy of LMWH to prevent arterial throm-sis is a point of debate. Although some studiesarly have found LMWH to be a less effectiveatment than traditional heparin in reducing thequency of arterial thrombosis,46,47 others have re-rted better or equal results.34,48 In a rabbit modelang et al48 observed a 50% increase in the patencyarterial anastomoses with LMWH in comparisonth no anticoagulation, but observed no differencethe patency of small venous anastomoses.The side-effect profile of LMWH is superior tofractionated heparin. In addition to causing fewermatomas LMWH has higher bioavailability (85%mpared with 10%), a longer plasma half-life, aady dose-response relationship,34,49 and causeser cases of thrombocytopenia compared with un-

ctionated heparin.25,50,51 Thus LMWH producesiable anticoagulation over a longer period of timethout the need for monitoring.49 After surgeryWH can be administered on an outpatient basis,

ich reduces the length of hospitalization time.

Low molecular weight heparin has a lesser effecton

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Askari et al / Anticoagulation in Microsurgery 839APTT than does unfractionated heparin. Thislue was found to be 3-fold lower for the lowestse of dalteparin with distinct antithrombotic effect0 U/kg) compared with the same dose of unfrac-

nated heparin.34 Therefore the level of activity ofWH is expressed best as units of antiactivated

tor X (factor Xa) activity instead of APTT.52 In amodel Ritter et al47 showed that a single injectioneither unfractionated heparin or LMWH just be-e pedicle division results in a similar anastomotictency and flap survival rate. Both increased APTTd antifactor Xa levels but LMWH had a moreminent increase on antifactor Xa, less of anrease in APTT, and no bleeding complications

mpared with unfractionated heparin. In additionprotective effects of LMWH include antithrom-

-independent effects such as the release of tissuetor pathway inhibitor, interactions with heparin

factor II, and platelet factor 4.45 Therefore attemptsstandardize LMWHs on the basis of anti-Xa activityve not been completely successful. This explains theerent difficulty in determining equivalent doses of

fractionated heparin to LMWHs. The pharmaco-ic profiles and efficacies of LMWHs vary; there-e success with one LMWH at a certain dose doest generalize to the whole group.Similar to unfractionated heparin the applicationtopical LMWH minimizes systemic side effects.en et al100 examined the effects of topical heparind topical LMWH (enoxaparin) on the patency ofastomosed vessels. The thrombosis rate for the firstdays was reduced significantly after either treat-nt in comparison with saline irrigation. They did

t find a statistical difference in patency or bleedingtween unfractionated heparin and LMWH.34 Lowerses (2 mg/kg) of subcutaneous LMWH (enoxaparin)re most effective at dilating capillaries (by 33%)thout bleeding complications in an animal model.53tas et al53 reported significant capillary dilation incremaster muscle 5 hours after administration of 2/kg and 4 mg/kg LMWH. The efficacy of higherWH doses (8 mg/kg) was no different than con-

l, but caused markedly increased bleeding. Lowerses of LMWH increase functional capillary perfu-n at the microcirculatory level of a rat cremasterscle flap without increased propensity for bleed-in the predissection and postdissection period.

xtranxtrans are a group of variously sized polysaccharidest are synthesized from sucrose by Leuconostoc mes-nly by microsurgeons to decrease vascular throm-sis. The antithrombotic effect of dextran isdiated through its binding to erythrocytes, plate-s, and vascular endothelium, increasing their elec-negativity and thus reducing erythrocyte aggrega-n and platelet adhesiveness. Dextrans decreasetelet adhesion by decreasing factor VIII-Ag (von

illebrands factor). Platelets coated in dextran aretributed more evenly in a thrombus and are boundcoarser fibrin, which simplifies thrombolysis. Byibiting -2 antiplasmin, dextran also serves as asminogen activator in thrombolysis.54,55 Larger

xtrans that remain in blood vessels act as potentmotic agents to reverse hypovolemia.56,57 Volumepansion causes hemodilution, which improvesod flow and further increases patency of micro-

astomoses. No difference has been observed in thetithrombotic efficacy of intra-arterial versus intra-nous dextran administration.36The varying size of dextran, from 10 to 150 kd,ults in prolonged antithrombotic and colloidal ef-ts.56 Larger dextrans are excreted poorly from theney and remain in the blood for weeks until theymetabolized.58 Dextran-40 (molecular weight, 40

) is the most popular dextran for anticoagulation.ose to 70% of Dextran-40 is excreted in the urinethin the first 24 hours after intravenous infusiond the remaining 30% is retained for several moreys, prolonging its effects.59,60Although there are relatively few side effects as-ciated with dextran use, they can be very serious.ese include anaphylaxis, volume overload, pulmo-ry edema, cerebral edema, or platelet dysfunc-n.56,61,62 An uncommon but major complication ofxtrans osmotic effect is acute renal failure.63,64 Aect toxic effect on the tubules and glomeruli orraluminal hyperviscosity are 2 proposed mecha-ms.65,66 Patients with a history of diabetes melli-, renal insufficiency, or vascular disorders are atatest risk. Brooks et al64 recommended avoiding

xtran therapy in patients with chronic renal insuf-iency and a creatinine clearance rate of less thanmL/min. In a prospective randomized comparisondextran- and aspirin-related complications in 100tients undergoing microsurgical flap reconstruction

head and neck malignancy, aspirin and dextranre equally efficacious in preventing flap failure.tients on dextran, however, had a 3.9- to 7.2-foldreased relative risk of systemic complications af-48 and 120 hours of dextran infusion, respec-

ely. Because the benefits of dextran prophylaxis

do not outweigh the risks, dextran is a less commonlyus

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840 The Journal of Hand Surgery / Vol. 31A No. 5 MayJune 2006ed anticoagulant therapy.67

pirinconstructive surgeons frequently use aspirin (ace-salicylic acid [ASA]) in the perioperative period toprove flap survival. Aspirin acetylates and inhibits

platelet enzyme cyclooxygenase, impeding ara-idonic acid breakdown to thromboxane and pros-yclin. Thromboxane is a potent vasoconstrictort induces platelet aggregation and prostacyclin is a

sodilator that inhibits platelet aggregation. There isidence that aspirin impairs thrombin generationd reactions catalyzed by this enzyme at the site ofastomosis.68 Perioperative administration of aspi-is known to prevent microvascular thrombosis at

th anastomoses sites, although it is less effectiven heparin.69 Cooley et al10 have shown that intra-

nous heparin yields higher patency compared withterically delivered aspirin. Assessment with anning electron microscope proved that more fibrin

cumulates in aspirin-treated vessels and moretelets aggregate in a heparin-treated group.10The timing of aspirin administration relative to thee of surgery alters efficacy. Kort et al37 did not

d any protective effect of aspirin administered 30nutes before surgery in rats. Similarly periopera-e administration of oral aspirin at 30 mg/kg in a ratombosis model did not provide antithrombotictection at 24 hours.70 The administration of aspi-(4 mg/kg) 10 hours before surgery resulted in a

nificant increase in patency and decreased the rateplatelet aggregation.71 In this study a single doseASA given before surgery resulted in a 2-foldrease in vessel patency at 1 week after anastomo-compared with control. Another study measuredprotective effect of systemic aspirin (adminis-

ed orally) in the maintenance of rat vein grafttency when administered for 1 week before sur-ry.72The protective effect of aspirin doubles when co-ministered during surgery with another antiplateletent, ticlopidine.73 Similarly the combination ofA with dipyridamole results in better venous pa-cy than heparin alone (40% compared with 6.7%)

d provides less arterial protection (6.7% comparedth 73.3%) 1 day after surgery. The combination of3 provides the best arterial and venous antithrom-

tic protection.8 In their search for the ideal aspirinse Peter et al74 found that low-dose aspirin (5/kg, infused intra-arterially immediately after ar-ial and venous anastomosis in a rat model) reducesanastomoses and results in better microcirculationough the muscle flap. Low-dose aspirin is pre-red by many surgeons because it does not affectdothelial and smooth muscle cyclooxygenase. As ault prostaglandin I2 (platelet antagonist and vasodi-or) production is unaffected and there are fewer sys-ic side effects.75

The same mechanisms that make aspirin a power-antithrombotic tool also can cause major prob-s. Platelet dysfunction results in increased blood

s during surgery, which increases transfusion andoperation rates.76 Experimentally desmopressin islpful to reduce thrombus formation and increaseerall platelet function after aspirin use.77 Otheririn side effects stem from its nonselective inhi-

ion of cyclooxygenase. Cyclooxygenase-I hasen referred to as the housekeeping enzyme becauseis expressed in many normal tissues in the bodyd regulates functions such as blood flow to theney and protection of gastric mucosa.78 By affect-the gastric mucosa and reducing platelet aggre-

tion aspirin can cause serious gastrointestinaleding. This risk is dose dependent and a low-doseimen (75 mg/d) minimizes the risk for bleeding.79wer cyclooxygenase-IIselective inhibitors are as-

ciated with fewer renal and gastric side effects butnot prevent platelet aggregation, therefore they do

t have a role in anticoagulation.80

rombolyticsrombolytic agents available for clinical use in-de streptokinase, urokinase, and tissue-type plas-nogen activator. Their efficacy in reversing micro-scular thrombosis is well documented in theimal model.81,82 Human studies are available butnt. In a retrospective multi-institutional study Yiial83 reported no significant improvement in pa-cy with the use of thrombolytic therapy in free-p salvage; however, Rooks et al36 reported that forestablished thrombus, urokinase results in markedprovement in patency compared with heparin andxtran. They reported an advantage to intra-arterialer intravenous administration of thrombolytics be-use intra-arterially delivered urokinase results innificantly greater efficacy (100% for intra-arterial40% intravenous). Because most human studiesk at small study populations there are no definitive

nclusions on the relative efficacy and appropriatesing of thrombolytics; however, it is known thatp salvage is most successful on the first postoper-ve day compared with postoperative day 2 and

beyond.83,84 Thrombolytic agents are associated witha r

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Askari et al / Anticoagulation in Microsurgery 841isk for bleeding but this risk can be minimized byining the venous effluent to prevent systemic ex-

sure to the agent.85

her Agentsedical scientists continue to search for new anti-ombotic and anticoagulant therapies that maxi-ze benefits while minimizing adverse effects. Thecacy of these agents was tested primarily in the

rdiovascular setting and only recently are theseents being investigated in microsurgery.Hemorrheologic agents such as pentoxifyllineTX) (Trental; Hoechst-Roussel Pharmaceutical,., Somerville, NJ) typically are used to treat

ronic occlusive arterial disease. They augmentod flow by vasodilating vessels, inhibiting platelet

gregation, and reducing fibrinogen levels. In addi-n PTX decreases blood viscosity by increasingthrocyte deformability, which improves tissue

rvival.86 The combination of these effects resultsimproved microcirculation and oxygenation in

rious flaps.87 Because PTX requires a 2-week win-w before the drug is effective, a 2-week preoper-ve regimen is necessary. In a randomized blindeddy to determine the efficacy of thromboprophy-tic LMWH and pentoxifylline in the rat microvas-lar free groin flap model, Murthy et al88 reported atistically significant improvement in arterial pa-cy with both LMWH and pentoxifylline, but notcombination. Inconsistent and insufficient human

ta make the prophylactic use of PTX in microsurgeryperimental.Recently recombinant hirudin, a compound origi-lly isolated from medicinal leeches, has been usedan anticoagulant. A specific thrombin inhibitor,udin is more potent than heparin without adverselyecting platelets.89 Hirudin can enter smalleraces inside microthrombi because it does not re-ire a cofactor, and therefore is smaller (7,000 d)n the bulky heparinantithrombin III complex.90ilar to heparin, however, hirudin can cause sig-

cant bleeding when administered systemically.89et al40 reported that a high concentration of top-l recombinant hirudin (750 g/mL) results in sig-cantly increased patency at 7 days (75% com-

red with 13.3% in the control group) with minimaleding in a rabbit microanastomosis model.Tissue factor pathway inhibitor (TFPI), a naturallycurring protein, blocks the tissue factor pathway ofagulation. It forms complexes with tissue factorIa and Xa, thus inhibiting the coagulation cas-Corp., Emeryville, CA) is more effective thanparin when added to irrigation solution used onombus-prone rabbit arteries.92 In a multicenter,ltinational, blinded, randomized, phase II studyouri et al14 found that intraluminal irrigation with

concentrations of SC-59735 (0.05 mg/mL) re-lted in a flap failure rate similar to treatment withher high-dose SC-59735 (0.15 mg/mL) or heparin0 U/mL). Irrigation with low-dose SC-59735,

wever, resulted in a marked incidence of hema-a formation compared with high-dose SC-59735

heparin. Thus they suggested that a lower dose ofombinant human TFPI improves flap survivalile minimizing the formation of postoperative he-tomas.Studies of Iloprost (CoTherix Inc., San Francisco,) report almost twice the rate of patency afterection, repair, and re-anastomosis of thrombosedastomoses.37,93 The difference is only statisticallynificant when vein grafts were used. Illoprost,wever, is less effective than systemic heparin atintaining patency at sites of vein graft re-anasto-sis.93

In 1988 Nichter and Bindiger94 found that treat-nt with ibuprofen and indomethacin markedly im-ved micrograft patency in a carotid rat model withsignificant difference when compared with aspi-

. Similarly the use of toradol (ketorolac) has beenorted when aspirin was contraindicated.95 Finally,

rioperative oral ticlopidine, a known platelet inhib-r, has been shown to be more effective at main-ning patency at both 1 hour and 1 week in a rabbitdel in comparison with aspirin (45% and 15%

tency rates at 1 hour and 1 week, respectively, forlopidine compared with 35% and 10%, respec-ely, for aspirin).73 The greatest increase in patencympared with control at 1 week occurred whenirin and ticlopidine were administered concur-tly, as opposed to when either agent was givenividually (20% patency at 1 week).

inical Studiesspite refined microsurgical skills and antithrom-tic therapeutic options, 6% to 25% of microsurgi-l cases result in re-operation because of thrombosisvascular anastomoses.96,97 Research in this fields been performed primarily in animal models.me researchers have suggested that the rodentdel has a uniquely higher rate of recanalization inombosed veins, which calls for caution in extrap-ting rodent data to human problems. There is a

paucity of data in the literature comparing anticoag-ulacu

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842 The Journal of Hand Surgery / Vol. 31A No. 5 MayJune 2006tion options in human microsurgery. Thereforerrent recommendations for microsurgical anticoag-tion therapy are based on extrapolations of con-ting animal data and scant human studies.

Recent literature examines the current state of thein anticoagulation for microsurgery. A 2001 arti-by Conrad and Adams98 reviewed the actions of

xtran, aspirin, and heparin and recommended an-oagulation regimens for free flaps and replants.ey recommended preoperative and postoperativeewed aspirin daily for 2 weeks, intraoperative hep-nized saline irrigant, and a heparin bolus of 50 to0 U/kg before releasing the clamps. For replantsnrad and Adams98 also recommended Dextran-400.4 mL/kg/h, weaned off by postoperative day 5.In 2001 Pederson99 recommended for replants thee of an indwelling axillary catheter to deliver mar-ine for 5 days to produce a chemical sympathec-

y, the use of chlorpromazine as a peripheral va-dilator and sedative for 3 to 5 days, and the use of5-mg aspirin for 3 weeks. His recommendationsre not based on specific animal studies and weret the results of large outcomes studies of differentthods of anticoagulation for microsurgery.The only human study to look at this issue recentlys the previously discussed study by Khouri et al.14is was a 6-month prospective study of 23 surgeonso performed 493 free flaps. This study looked atny variables and provided associations betweenferent methods of anticoagulation and flap failurees. Khouri et al14 reported that only subcutaneousparin significantly differs in its clinical effect, asbcutaneous heparin decreased the odds ratio forombosis by 27%. No other antithrombotic regi-n had a statistically significant association withnical outcomes.Khouri14 reported several other trends that weret statistically significant. There was flap failure in% of patients who were given preoperative sys-ic therapy such as heparin, aspirin, or dextran.

tients without preoperative systemic therapy expe-nced 4.6% flap failure. In addition, patients whoeived intraoperative systemic heparin as a part oformal prophylactic anticoagulation protocol had a% flap failure rate versus 2.9% when no heparins used in the normal protocol. There were noociations with outcomes reported for patients whoeived dextran, aspirin, or heparinized intraopera-e irrigation.It should be noted that Khouris study14 was notsigned specifically to compare different methodsch surgeon used the anticoagulation protocol withich he or she was accustomed. Therefore each

rgeon used an anticoagulation regimen appropriatehis or her specific technique. This confoundingtor may invalidate conclusions drawn from thisdy.Although no data clearly support any specific an-oagulant for microsurgery, this review provides ammary of current data to assist the clinician insigning a rational approach to anticoagulation forcrosurgery. The timing of anticoagulation, route ofticoagulation, the use of combination therapy, andividualization of microsurgical anticoagulation tosurgical technique may improve future microsur-

al outcomes.The appropriate timing of anticoagulation therapyximizes its effectiveness. The first 2 days after

rgery are crucial in anticoagulation because thejority of clots form during this time. The best timeinitiate anticoagulation treatment, however, mayt necessarily be on those days. In their prospectivetcomes study of free-flap surgeries, Khouri et al4orted a 2-fold decrease in flap failure (this was nottistically significant) with preoperative use of as-in, dextran, or heparin. A significant antithrom-tic effect is observed after a single dose of aspirinen several hours before surgery.71 Anticoagula-n is not popular secondary to an increased risk forraoperative bleeding and most surgeons are in-ned to initiate anticoagulation after the procedure.ouri et al4 concluded that the postoperative use of

bcutaneous heparin is superior to any other peri-erative administration. Similarly the route of anti-agulant delivery is a subject of interest. The effectslocal delivery may differ from the systemic deliv-of similar agents.

Another part of the solution may lie not in choos-the right antithrombotic therapy but in finding the

st combination of agents. In the conclusion of theirdy Peter et al74 suggested using systemic low-doseirin with heparin locally for irrigation of mi-vessels to maximize antithrombotic effect whilenimizing side effects. Indeed future research mayst be directed toward a combination of popularlyed therapies rather than comparing single agentsth each other.The lack of progress in understanding how best toticoagulate microsurgical patients may stem from theersimplified attempt to apply a one-size-fits-all ap-ach to microsurgical patients. A review of the di-

rse anticoagulation protocols used in various study

models and of the inconsistent outcomes reported forsiman

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Corresponding author: W. P. Andrew Lee, MD, Division of PlasticSurSca

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Askari et al / Anticoagulation in Microsurgery 843ilar treatments indicates a need for individualizedticoagulation therapy. In an effort to elucidate indi-ual risk Olsson et al97 investigated coagulation andrinolysis during various microsurgical tissue trans-s and found an association between specific plasmarkers (thrombin-antithrombin III complex and pro-ombin fragment-1.2) and flap failure. Preoperativepercoagulability and excessive bleeding during sur-ry were predictors of re-operation.97 By measuringch patients coagulability before surgery using coag-tion markers the surgeon could tailor the anticoagu-ion regimen. With close postoperative follow-upaluation of the same markers it may be possible touce the need for re-operation.In addition, anticoagulation regimens could beapted to each surgical procedure. For example,AM flap surgery has a lower incidence of postop-tive thrombosis (36%) whereas the use of veinfts or transfer of a flap to a chronic wound bedreases the odds of the same event (2.5 and 2.9-d, respectively).9 The amount of bleeding duringrgery is associated with an increased postoperativek for thrombosis, likely owing to activation ofagulation pathways.97 This observation under-res the importance of proper intraoperative hemo-sis. A combination of patient status, surgical plan-g and approach, and up-to-date knowledge of

ticoagulant agents and their efficacy is important ininishing the incidence of thrombosis and postop-

tive flap failure.The currently available data are not adequate tovelop a rational evidence-based approach to anti-agulation for microsurgery. Animal studies exist tofend or refute the use of almost any pharmacologicans of anticoagulation for microsurgery. Insuffi-nt human outcomes data exist to corroborate theseimal studies. The data from Khouri et al14 suggestt the only method of anticoagulation that is statis-ally significantly associated with a decreased oddsthrombosis is subcutaneous heparin. Based on

blished data no other single method has an obviousvantage. This indicates that an excellent microsur-al technique is the critical factor in consistentlytimal microsurgical outcomes. Until reliable hu-n outcomes data are available the choice of an

ticoagulant to complement the surgical techniqueains a matter of personal experience and inter-

tation of existing studies.

benefits in any form have been received or will be received from amercial party related directly or indirectly to the subject of this

cle.gery, University of Pittsburgh School of Medicine, 3550 Terrace St,ife Hall, Suite 690, Pittsburgh, PA 15261; e-mail: leewpa@upmc.edu.opyright 2006 by the American Society for Surgery of the Hand363-5023/06/31A05-0025$32.00/0oi:10.1016/j.jhsa.2006.02.023

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846 The Journal of Hand Surgery / Vol. 31A No. 5 MayJune 2006

Anticoagulation Therapy in Microsurgery: A ReviewOverview of Thrombosis in MicrosurgeryAntithrombotic TherapyHeparinLow Molecular Weight HeparinsDextranAspirinThrombolyticsOther Agents

Clinical StudiesReferences