Percutaneous Ultrasound-Guided Thrombin Injectionfor the Treatment of PseudoaneurysmsAlex Powell, MD, James F Benenati, MD, Gary J Becker, MD, Barry T Katzen, MD, Gerald Zemel, MD

Because of the ever-increasing use of percutaneous inter-vention for coronary and peripheral disease and the largenumbers of diagnostic procedures being performed eachyear, postcatheterization pseudoaneurysms (PSAs) arebecoming increasingly prevalent.1-3

With the introduction of the landmark technique ofultrasound-guided compression, Fellmeth and col-leagues4 revolutionized the treatment of PSAs. Unfortu-nately, ultrasound-guided compression is associatedwith a relatively low overall success rate of 42% to 100%,which is even lower in patients who are on anticoagula-tion therapy.5-7 In addition, procedural pain necessitatesearly termination and procedure failure in up to 10% ofpatients. Finally, long procedure times, ranging from 10to 300 minutes, result in both patient and physiciandissatisfaction with the procedure.

Topical bovine-derived thrombin has been in wide-spread surgical use for local hemostasis for years.Thrombin serves to propagate the final pathway of thecoagulation cascade by initiating fibrinogen to formthrombin. Although the original description of percuta-neous thrombin injection for the treatment of PSAs wasfirst made by Cope and Zeit8 in 1986 and followed byWalker and colleagues9 in 1987, it was not until theaddition of ultrasound guidance by Liau and col-leagues10 that the technique gained widespreadacceptance.

The purpose of this article is to review the techniqueand the basis for the use of thrombin in the treatment ofPSAs. Results of all published series to date, complica-tions, and treatment strategies will be discussed.

TechniqueThe PSA is first interrogated with both gray-scale andcolor-flow imaging. It is imperative that the relationshipof the PSA to the native vessels is understood. Duplex

imaging is necessary as well to assess for an associatedarteriovenous fistula. The PSA and its neck should alsobe assessed for size and for the presence of septations/loculations. Typically, a 7.5-MHz linear probe is usedfor the procedure, although lower-frequency probes maybe necessary for deeper tissue penetration in selectedpatients. Careful pre- and postprocedure documenta-tion of the pulses distal to the site to be injected is re-quired as well.

The site and the ultrasound probe are then preparedand draped using standard sterile techniques. The skinoverlying the PSA is typically anesthetized, althoughsome authors prefer to minimize the number of needlesticks and proceed directly with thrombin injection. A19- to 25-g, 2.5-inch needle is most frequently used,although sometimes the depth of the PSA requires theuse of a longer needle of a similar gauge. Either a linearor transverse orientation of the needle relative to theprobe can be used. This should be at the operator’s pref-erence. Likewise, some authors advocate the use of aneedle guide, but again, this is according to operatorpreference. Regardless of the approach, it is imperativethat the needle tip be absolutely and unequivocally iden-tified before thrombin injection is performed. Adjunc-tive procedures favored by some authors to increase nee-dle conspicuity include the injection of saline or a fewmicrobubbles of air, but a small clot frequently forms onthe needle tip from the exposure of blood to thrombin inthe needle, making the visualization of the needle tiprelatively easy and obviating the need for adjunctive pro-cedures. It cannot be stressed strongly enough that theprocedure should not proceed until the needle tip isvisualized with certainty.

The thrombin is then reconstituted to a concentra-tion of 1,000U/mL, although some authors,11 includingthose at this institution, favor further dilution to 100U/mL. The thrombin is then allocated into several 1-mLsyringes. One-milliliter syringes are favored, becausethey provide much more precise delivery than larger sizesdo.

Under direct visualization, the thrombin is then

No competing interests declared.

Received June 6, 2001; Revised August 21, 2001; Accepted August 23, 2001.From the Miami Cardiac & Vascular Institute, Miami, FL.Correspondence address: Alex Powell, MD, Miami Cardiac & Vascular Insti-tute, 8900 N Kendall Dr, Miami, FL 33176.

S53© 2002 by the American College of Surgeons ISSN 1072-7515/02/$21.00Published by Elsevier Science Inc. PII S1072-7515(01)01100-0

slowly injected. Imaging can be with either gray-scale orcolor-flow ultrasound. With gray-scale imaging, anechogenic clot rapidly forms at the needle tip and rapidlyexpands to fill the entire cavity. Under color-flow imag-ing, there is an initial burst of color as the thrombin isinjected and a rapid diminution once thrombosis oc-curs. Once total thrombosis is suspected, a detailed in-terrogation of the PSA is necessary to assess for any re-sidual flow. Occasionally, a separate loculation isdetected that requires repeat injection. Regardless of theconcentration, typical total injection volumes rangefrom 0.3 to 3mL.

The patient is then placed on bed rest for 4 to 6 hours.A repeat ultrasound is performed the next day. Typically,a 1- to 2-week postprocedure ultrasound is obtained aswell.

RESULTSThe results of all series published to date are summarizedin Table 1. Studies are included in this table only if theyrepresent the overall author experience at the time ofpublication. Those reports in which only a subset ofpatients or a specific complication are reported are notincluded in this table. Success rates are given as proce-dural rather than technical success. With those authors12

who reported their results as initial technical success,their reported results have been changed to conform tothis standard format. In those cases where there was arecurrent PSA on the 1-day followup examination, a casewas determined to be a success if subsequent reinjectionproved successful. Likewise, the case was determined tobe a failure if it was not possible to successfully treat the

recurrence with additional thrombin injections despitethe initial technical success. Almost all of the cases in-volve femoral PSAs, but several authors have includedthe results of postcatheterization PSAs of the upper ex-tremities. The results of treatment of four cases of noni-atrogenic posttraumatic PSAs are included by Kang andcolleagues.12 It should be noted that other authors22,23

have reported treating iatrogenic PSAs of the axillaryand subclavian arteries, and Clark and Abraham24 re-ported two cases of thrombin injections into brachialarteries adjacent to hemodialysis grafts. Thesereports22-24 are not included in the overall analysis be-cause they are case reports rather than an overall institu-tional experience.

Overall, the various authors in Table 1 have reportedon a total of 319 patients. Of these patients, 309 weresuccessfully treated with thrombin injection, for anoverall procedural success rate of 97%. Complicationswere reported in 3 of these 319 patients, giving a com-plication rate of 0.94%.

Although not individually reported, a significant per-centage of the patients either were fully heparinized orwere being treated with antiplatelet agents. The successrate was deemed to be independent of anticoagulationstatus.

Although there were no independent predictors ofprocedural failure, several studies report a trend (but notstatistical significance) of an increased failure rate withlarger-sized PSAs. It has been our experience and that ofseveral others that the presence of loculations and resid-ual flow at the termination of the initial procedure leadto early failure/recurrence. With additional experience,

Table 1. Summary of the LiteratureFirst author Patients (n) Success (n) Complications (n) Notes

Liau10 5 5 0 Original report with ultrasoundKang12 83 81 1 Nine nonfemoral casesTaylor11 29 27 0 Low dose (100U/mL); no anesthesia givenLa Perna13 70 66 0 Three early recurrences, all successfully treatedBendick14 11 11 1 Nonocclusive brachial thrombosisTamim15 10 10 0 10- to 150-s treatment timeBrophy16 15 15 0 All patients had failed ultrasound-guided compressionPaulson17 26 25 0 96% success versus 74% for ultrasound-guided compressionPezzullo18 23 22 1 Loss of distal pulses with spontaneous resolutionHughes19 9 9 0 2,000U/mL usedVermeulen20 8 8 0 500U/mLLennox21 30 30 0 Over 50% of patients anticoagulatedTotals 319 309 3

S54 Powell et al Ultrasound-Guided Thrombin Injection J Am Coll Surg

it has become clear that it is necessary to treat all locula-tions with direct injections should residual flow remain.It has been our experience that older PSAs are moreprone to loculations and so present a potential for pro-cedural failure if complete thrombosis of the entire PSAis not achieved. Parenthetically, one patient with a 4.5-month-old PSA has been treated in our series. La Pernaand colleagues13 report treating a PSA of the sameduration.

Although treatment times were not uniformly re-ported, it has been the experience of all authors whocomment that once needle tip position has been con-firmed, the time from thrombin injection to completethromboses is frequently less than 1 minute. In thosecases where an additional loculation has to be injected,the procedure takes slightly longer, but it has never ex-ceeded 10 minutes in our experience once the initialscanning and preparation have been completed.

DilutionThere is no significant difference in either the proce-dural success or the complication rate of those authorsusing a dilution of 100U/mL11 compared with thoseusing 1,000U/mL. Of interest, Kang25 makes the argu-ment that a low dilution may even be harmful. The basisfor this opinion is that a lower dilution may necessitatehigher than normal injection volumes. If the total vol-ume injected were to exceed the volume of the PSA, theninadvertent arterial injection could result. The data donot appear to support this argument. The injection vol-umes reported by Taylor and colleagues11 of 0.3-mL onaverage were far less than the PSA volume and, in fact,were on the lower end of the injection volumes reportedin the literature, despite a 10-fold dilution of the throm-bin. Despite this finding, the point does remain: regard-less of the dilution, the PSA volume should be obtained,and great care should be taken not to exceed the volumeof the PSA with thrombin injections.

ComplicationsOverall, the reported complication rate in this series is0.94%. It should be noted that the complication rate hasbeen calculated from all series in which both successesand failures have been reported. Several individual casereports detailing procedural complications25-27 havebeen reported as well. They are not included in the over-all complication rates, because their inclusion would un-fairly skew the data to a higher complication rate because

the authors have not included their success rates in thesereports. Obviously, these complications are of the ut-most importance and will be individually discussed. Thehighest individual complication rate is 9%, reported byBendick and colleagues,14 with most authors reportingno complications. The observed complications stemfrom two distinct processes. The most common re-ported complication is a thrombotic complication; therarer, but potentially just as significant, complicationappears to be immune mediated.

The most significant thrombotic complication re-ported to date is that reported by Lennox and col-leagues.21 In this case they report significant upper-extremity ischemia necessitating urgent surgical repairafter brachial artery injection in a 10-month-old boy. Areview of the case shows no clear indication for the com-plication, but some speculate that the small arterial size(2 to 3mm) may have contributed to the complication.Because of this, great caution in treating infants is sug-gested. It should be noted that Frush and colleagues28

successfully treated an 8-month-old patient with a com-mon femoral PSA.

The most significant adult thrombotic complicationwas recently reported by Sadiq and Ibrahim.27 They re-port a case of significant lower-extremity ischemia afterthrombin injection into a left femoral PSA. Subsequentangiography demonstrated extensive distal emboli.Catheter-directed rt-PA therapy at a rate of 2mg/h for13 hours was then initiated with subsequent completethrombus lysis. Interestingly, the PSA remained throm-bosed after the rt-PA administration. It is important tonote that the authors reported no deviation from theirstandard protocol in this case and were confident of theneedle tip location. A concentration of 1,000U/mL wasused, and a total of 1mL was injected, a volume far lessthan the PSA volume. This is an important case to note.Although the other significant complications occurredin smaller arteries, this is not the case with this report, soit must be said that although smaller arterial size maylead to a higher potential complication rate, injection ofthe femoral artery is not without risk.

Other thrombotic complications that have been re-ported so far have followed a more benign course. Pez-zullo and colleagues18 reported one case of loss of thedorsal pedis pulse with subsequent spontaneous resolu-tion. Kang and colleagues12 reported one case of upper-extremity ischemia after brachial artery injection thatresolved after an IV heparin bolus. In review, Dr Kang

S55Vol. 194, No. S1, January 2002 Powell et al Ultrasound-Guided Thrombin Injection

and his colleagues12 attributed this complication to in-advertent native arterial injection in an effort to treatresidual flow within the neck of the PSA. Finally, Ben-dick and colleagues14 reported a small, nonocclusive,and asymptomatic thrombus within the native brachialartery 1cm distal to the PSA site (no treatment given).

Recently, Pope and Johnston26 have made the firstreport of a serious immune-mediated reaction to theinjection of thrombin for PSA treatment. In this report,they describe an anaphylactic reaction necessitating in-tubation and aggressive supportive care in a patienttreated with 500U of thrombin for a femoral PSA. Thepatient’s history was significant for end-stage renal dis-ease, and the patient had previously had multiple appli-cations of topical thrombin for hemostasis at the dialysisgraft access site. Subsequent skin-prick testing of thispatient showed a significant positive reaction.

Although Pope and Johnston’s26 is the first report inthe literature detailing an immune-mediated reaction tothrombin injection for a PSA, immune-mediated re-sponses to multiple previous thrombin exposures havebeen documented.29-31 Tadokoro and colleagues32 ana-lyzed five patients who developed reactions to thrombinafter repeated exposure. They found significantly higherimmunoglobulin E levels in all of these patients. Al-though the immunoglobulin E antibodies were found tobe directed against a bovine protein contaminant in thethrombin preparation, it still illustrates the continuedpotential for a serious immune-mediated response inpatients with repeated thrombin exposure.

As a result of their experience and a review of theliterature, Pope and Johnston26 now recommend takinga careful history from those patients being considered forpercutaneous thrombin injection. In those patients witha previous exposure history, skin-prick testing is recom-mended. If no local erythema or swelling occurs at thesite within 15 minutes, patients can undergo thrombininjection for their PSA.

In addition to the immunoglobulin E immune-mediated reaction, another potential immune-mediatedreaction has been reported in the literature.33,34 In thesecases, patients who received repeated injections of bo-vine thrombin developed antibodies to bovine factor V.These antibodies may then react with human factor Vand result in a coagulopathy. It should be noted that nosuch reactions have been reported in the literature todate in the subset of patients who have received throm-bin injections for PSA treatment.

DISCUSSION

Since the first descriptions of ultrasound guidance forthe percutaneous injection of thrombin into PSAs, thetechnique has quickly gained widespread acceptance andis rapidly replacing ultrasound-guided compression asthe method of choice for the treatment of PSAs. Theliterature review provided in this work demonstrates anoverall procedural success of 97% in those series re-ported in the literature to date. Additionally, the successof the procedure appears to be independent of the anti-coagulation status of the patient, a significant differencewhen compared with the technique of ultrasound-guided compression.

The recent appearance of several case reports aboutcomplications associated with this procedure does meritdiscussion. Although some cases of thrombotic compli-cations appear to be related to the inadvertent injectionof the native arteries or perhaps to a small artery size,others are not related to these causes, and the cause ofthese complications is uncertain. Perhaps the further di-lution of thrombin to 100U/mL will help to reduce thecomplication rate, but this is only speculation at thispoint. It will take a significantly greater experience todraw any significant conclusions on the definitive ben-eficial effects of this dilution. Nonetheless, the authorsusing this lower dilution have reported no complica-tions, nor does it appear to diminish the effectiveness oftreatment.

The immune-mediated complications associatedwith this treatment are potentially quite troubling.Clearly, it has been demonstrated that some patientshave developed antibodies as a result of repeated throm-bin exposure and are at risk for potential immune-mediated complications. Although it may be somewhatunclear if the reaction is to the thrombin or to a contam-inant, the point remains the same: until further knowl-edge is gained, anyone who has had a previous exposureto thrombin should likely be tested for a potential aller-gic reaction.

In the appropriate situations, ultrasound-guidedthrombin injection is clearly a highly successful proce-dure with a low overall complication rate. In addition,when compared with ultrasound-guided compression,the procedure takes a fraction of the time, is less painfulto the patients, and is successful even in those patientswho are on full anticoagulation therapy.

S56 Powell et al Ultrasound-Guided Thrombin Injection J Am Coll Surg

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