portal vein thrombosis is a potentially preventable complication in clinical islet transplantation

American Journal of Transplantation 2011; 11: 2700–2707Wiley Periodicals Inc.

C© Copyright 2011 The American Society of Transplantationand the American Society of Transplant Surgeons

doi: 10.1111/j.1600-6143.2011.03717.x

Portal Vein Thrombosis Is a Potentially PreventableComplication in Clinical Islet Transplantation

T. Kawaharaa, T. Kina, S. Kashkousha,

B. Gala-Lopeza, D. L. Bigama, N. M. Knetemana,

A. Kohb, P. A. Seniorb and A. M. J. Shapiroa,*

Departments of aSurgery and bMedicine, University ofAlberta, Edmonton, Alberta, Canada*Corresponding author: A. M. James Shapiro,[email protected]

Percutaneous transhepatic portal access avoidssurgery but is rarely associated with bleeding or por-tal venous thrombosis (PVT). We herein report ourlarge, single-center experience of percutaneous isletimplantation and evaluate risk factors of PVT and graftfunction. Prospective data were collected on 268 in-traportal islet transplants (122 subjects). A portal ve-nous Doppler ultrasound was obtained on Days 1 and 7posttransplant. Therapeutic heparinization, completeablation of the portal catheter tract with Avitene pasteand limiting packed cell volume (PCV) to <5 mL com-pletely prevented any portal thrombosis in the mostrecent 101 islet transplant procedures over the past5 years. In the previous cumulative experience, partialthrombosis did not affect islet function. Standard livervolume correlated negatively (r = −0.257, p < 0.001)and PCV correlated positively with portal pressure rise(r = 0.463, p < 0.001). Overall, partial portal throm-bosis occurred after 10 procedures (overall incidence3.7%, most recent 101 patient incidence 0%). Therewere no cases of complete thrombosis and no patientdeveloped sequelae of portal hypertension. In conclu-sion, portal thrombosis is a preventable complicationin clinical islet transplantation, provided therapeuticanticoagulation is maintained and PCV is limited to<5 mL.

Key words: Islet transplantation, portal vein thrombo-sis, risk factors, standard liver volume

Abbreviations: AUC, area under the curve; BSA, bodysurface area; IE, islet equivalents; PCV, packed cell vol-ume; PVT, Portal vein thrombosis; SLV, standard livervolume; SUITO, secretory unit of islet transplant ob-jects.

Received 06 April 2011, revised 28 June 2011 andaccepted for publication 02 July 2011

Introduction

The outcomes and safety of clinical islet transplantationhave improved considerably in the past decade (1–4).The attraction of a percutaneous day-case procedure thatavoids general anesthesia, prolonged hospitalization andpain may be preferential to the major alternative approachof vascularized whole pancreas transplantation, but thispremise is dependent upon the percutaneous technique,being both safe and free from complications. The risk ofboth bleeding and portal venous thrombosis (PVT) havebeen well described previously but now may be entirelypreventable with a combination of systemic heparin, lim-ited islet cell volume and complete obliteration of the tran-shepatic catheter tract (5–8).

Complete thrombosis of the entire portal venous systemis the most feared complication of intraportal islet trans-plantation (9,10). However, complete thrombosis with se-quelae of chronic portal hypertension has now proven tobe an exceedingly rare complication.

We herein investigate the incidence of PVT in a large,single-center prospective series of 268 consecutive intra-portal islet transplants conducted over 11 years. We fur-ther analyze contributory factors leading to partial throm-bosis, including standard liver volume (SLV), packed cellvolume (PCV) and acute portal pressure rise after islettransplantation, assuming that a smaller liver volume wouldlikely have less capacity for embolized intraportal tis-sue. We further explore whether partial portal thrombo-sis is associated with detrimental loss of islet functionalreserve.

Methods

Patients

Between May 1999 and August 2010, a total of 278 percutaneous intra-portal islet-alone transplants were carried out in 127 subjects with unstabletype 1 diabetes at the University of Alberta. Those participating in the collab-orative islet transplant (CIT) trials (10 procedures, 5 subjects) were excludedfrom this analysis, as this data will be reported collectively when the CITtrials are completed. Of note, we did not encounter any portal thrombosis inthese 10 procedures. Therefore, 268 islet-alone transplants were analyzedin 122 subjects. The study was approved by the Health Research EthicsBoard of the University of Alberta, and all patients gave written consent toparticipate.

2700

Portal Thrombosis: Islet Transplant

Islet isolation and islet transplantation

Islets were prepared as described previously, using xenoprotein-free mediawith 35 units/kg of heparin (70 units/kg if PCV > 5 mL), and infused undergravity into the main portal vein (1). Access to the portal vein was achievedusing a percutaneous transhepatic technique under fluoroscopic guidance,as described previously (11–13). In brief, portal vein access was carried outusing 22-gauge Chiba needle and exchanged over a 0.018-inch guidewire fora 4Fr cannula (12). Portal venous pressure (mmHg) was measured by usinga pressure transducer (Medex, Hilliard, OH, USA) at intervals throughoutthe islet infusion. A Doppler ultrasound (Philips HDI 5000 color flow Dopplerultrasound machine or equivalent, with 2.0–2.5 MHz probe, Philips Health-care, Andover, MA, USA) was performed routinely within 24 h and repeatedon Day 7 to look for PVT, hematoma or intraperitoneal bleeding.

Insulin infusion and anticoagulation treatment after islet

transplantation

Intravenous insulin (1–2 units/h) was infused together with dextrose (10%)to maintain blood glucose levels between 4.1 mmol/L and 7.0 mmol/L for48 h posttransplant, as previously described (7). After discontinuing the in-travenous insulin infusion, subjects monitored capillary blood glucose seventimes per day and administered subcutaneous insulin aiming for prepran-dial glucose 4–6 mmol/L and postprandial glucose 5–8 mmol/L. Intravenousheparin was infused at a loading dose of 70 units/kg and delivered intrapor-tally mixed with the islet preparation, and a peripheral intravenous heparininfusion (3 units/kg/h) was initiated immediately after ablation of the tran-shepatic islet catheter tract while the patient was still in the radiology suiteand adjusted to keep the partial thromboplastin time between 70 s and90 s for 48 h after transplant. After this period, the subjects were givensubcutaneous low molecular weight heparin (enoxaparin, 30 mg twicedaily) for 7 days and aspirin 81 mg daily for 14 days. Before 2005, only35 units/kg heparin was given intraportally and no posttransplant infusionwas given.

Calculation of body surface area, body mass index and SLV

Body surface area (BSA) was calculated using Mosteller’s formula: BSA =√height(cm) × weight(kg)/3600 (14). Body mass index (BMI) was obtained

by using the formula: BMI = weight (kg)/square height (m) (15). The SLVwas calculated based on BSA by using the formula: SLV = −794.41 +1267.28 × BSA (16).

Calculation of secretory unit of islet transplant objects index

Secretory unit of islet transplant objects (SUITO) index was calculated usingthe formula: 1500 × (fasting C-peptide immunoreactivity [F-CPR; ng/mL] /[fasting blood glucose {mg/dL}–63]) (17). Average SUITO index in healthysubjects is designed as a score of 100.

Statistical analyses

Statistical comparisons between the groups were performed with the two-sample t-test or Mann–Whitney U-test, as appropriate for comparison ofthe two groups.

When both variable and outcome data were ordinal, correlations were per-formed using the Pearson’s correlation test and expressed as Pearson’scorrelation coefficient. All comparisons were two-tailed. A p-value < 0.05was considered to be statistically significant for univariate analysis. Multi-ple regression analyses were performed with SLV, change in portal venouspressure, transplanted islet cells, transplanted islet cells per kg and PCV,to account for confounding variable effect. The cutoff of PCV was deter-mined according to the risk of PVT after islet transplantation of a receiveroperating characteristic (ROC) curve, and was selected to achieve the bestsensitivity/specificity combination.

All statistical calculations were performed using SPSS (SPSS Inc., Chicago,IL, USA). Values for p less than 0.05 were considered statisticallysignificant.

Results

Characteristics of islet transplant recipients and

transplanted islet cells

Characteristics of recipients were summarized in Table 1.Recipients received a mean of 2.19 islet infusions per pa-tient (one transplant 12, two transplants 80, three trans-plants 24 and four transplants 6). A mean islet mass of404 999 islet equivalents (IE) were infused intraportallyper transplant (5908 IE/kg) in a mean PCV of 4.1 mL(range: 1.5–15.0 mL). Mean subject height and weightwere 169 cm and 67.5 kg, respectively. Mean calculatedSLV of recipients was 1484.4 cm3, ranging from 908.1 to2020.9 cm3.

Factors affecting portal venous pressure after islet

transplantation

The PCV correlated positively with change in portal venouspressure with r = 0.463 and p < 0.001 (Figure 1A). Also,SLV correlated negatively with change in portal pressure(r = −0.257 and p < 0.001; Figure 1B), with larger liversable to accommodate less perturbation in portal venouspressure.

Partial PVT after islet transplantation

There were no cases of complete thrombosis of the por-tal system and none of our 127 subjects have mani-fested signs of portal hypertension in up to 11 years offollow-up. Among the 268 islet transplantation procedures,10 cases (9 subjects, 3.7%) developed partial PVT, as

Table 1: Characteristics of recipients and transplanted islet celldata

Recipient and islet cell data

Recipient dataTotal transplant patients 122Total number of transplant

procedures268

Mean height (cm) 169 ± 9.1 (151–188)Median transplants 2.19 ± 0.68 (1–4): one

transplant (n = 12), two(n = 80), three (n = 24),

four (n = 6)Mean weight (kg) 67.5 ± 11.5 (44.2–100.0)Mean BMI (kg/m2) 23.6 ± 3.3 (16.5–40.0)Mean standard liver volume

(cm3)1484.4 ± 234.4

(908.1–2020.9)Islet cell data

Mean transplanted islet cells(IE)

404 999 ± 121 764(160 116–883 764)

Mean transplanted islet cells/kg(IE/kg)

5908 ± 1541 (2740–10 907)

Mean packed cell volume (mL) 4.1 ± 1.7 (1.5–15.0)

American Journal of Transplantation 2011; 11: 2700–2707 2701

Kawahara et al.

Figure 1: Factors affecting acute change of portal venous pressure after islet transplantation. (A) Correlation between packed cellvolume and change in portal vein pressure. (B) Correlation between standard liver volume and change in portal vein pressure.

Table 2: Characteristics of recipients with partial portal vein thrombosis after islet transplantation

Transplanted Transplanted Change inWeight BMI BSA SLV islet cell islet cell PCV Pre-PVP Post-PVP PVP

Cases (kg) (kg/m2) (m2) (cm3) (IE) (IE/kg) (mL) (mmHg) (mmHg) (mmHg) PVT

1 77.0 24.9 1.940 1664.4 413 178 5366 3.0 6 8 2 Right PVT2 57.6 20.5 1.637 1280.5 497 379 8633 9.0 8 36 28 Complete left

PVT3 60.7 23.1 1.654 1301.4 496 110 8173 5 12 20 8 PVT on anterior

branch of theright PV

4 54.4 23.9 1.511 1119.9 298 802 5493 8.0 13 20 7 Complete leftPVT

5 71.9 22.2 1.896 1608.1 349 930 4868 3.5 12 17 5 Partial PVT inright PV

6 55.7 24.1 1.533 1148.9 243 328 4369 5.5 13 19 6 Left PVT7 67.0 23.7 1.768 1446.6 315 470 4708 2.7 4 5 1 PVT on anterior

branch of theright PV

8 67.0 26.2 1.725 1392.2 511 621 7638 8.0 6 21 15 Left PVT9 60.0 22.8 1.644 1289.2 290 210 4837 3.0 14 14 0 Left PVT

10 69.0 26.0 1.767 1445.5 372 100 5393 7.0 11 28 17 PVT in the rightanterior andposteriorportal veinbranch

BMI = body mass index; BSA = body surface area; SLV = standard liver volume; IE = islet equivalent; PCV = packed cell volume;PVR = portal venous pressure; PVT = portal vein thrombosis.

summarized in Table 2 (case 3 and 9 represent the samesubject, with partial thrombosis on two occasions—nounderlying thrombophilia was uncovered). In all cases,the partial PVT resolved within a few weeks and didnot propagate. Anticoagulation with intravenous heparinand then coumadin was continued for the duration of 6months. Since 2005, we have ablated the hepatic catheterparenchymal tract routinely with Avitene paste. This singlemaneuver has substantially increased the safety of ther-apeutic heparinization after the procedure (8). After theintroduction of therapeutic heparinization and limiting the

PCV to less than 5 mL for each islet infusion, we have notexperienced any further cases of partial PVT in the sub-sequent 101 procedures over the most recent 4.5 years(Figure 2).

Functional assessment of transplanted islet cells by

SUITO index after PVT

We assessed the potential detrimental impact of a par-tial portal thrombosis on islet function by the SUITO

2702 American Journal of Transplantation 2011; 11: 2700–2707


Figure 2: Cumulative risk of por-

tal vein thrombosis and number

of islet transplant procedures per

year. Since 2005, intravenous heparin(70 units/kg) has been infused to keepthe partial thromboplastin time >60 sor 48 h after transplant and packedcell volume has been kept <5 mL. Noportal vein thrombosis has been ob-served in the most recent 5 years.

Figure 3: Evaluation of trans-

planted islet cells in the liv-

ers with or without portal vein

thrombosis by SUITO index.

No significant difference was ob-served between no portal veinthrombosis patients and portalvein thrombosis patients at (A) 5–7 days and (B) 1 month, after islettransplantation. Each symbol rep-resents an individual case.

index, a tool to evaluate function of engrafted islet cellsand predicts the possibility of insulin independence (17).We measured C-peptide and fasting blood glucose at 5–7days and at 1 month after islet transplantation (Figures 3Aand B).

As controls, we randomly selected a similar number ofage-, gender- and duration of diabetes-matched non-PVTsubjects undergoing similar islet transplant procedures atour center. There is no significant difference between con-trols (no PVT) group and PVT group in the number of trans-planted islet cells and the number of transplanted isletcells/kg (data not shown). To standardize the SUITO in-dexes, we report delta SUITO index, calculated from theSUITO index in each time point (5–7 days or 1 month post-transplant) minus SUITO index just before the transplant.No differences were observed between the non-PVT sub-jects and those experiencing partial thrombosis at 5–7 days(Figure. 3A; no PVT vs. PVT, 31.3 ± 10.2 vs. 29.9 ± 9.9:N.S.) or at 1 month (Figure 3B; no PVT vs. PVT, 20.4 ± 9.9vs. 33.4 ± 12.8: N.S.) posttransplant, indicating that par-tial thrombosis did not substantially affect the transplantedislet graft function.

Risk factors of PVT after islet transplantation

Univariate analysis revealed that the change in portal ve-nous pressure and PCV had significant correlations withPVT (p = 0.001 and p = 0.009, respectively; Table 3).Interestingly, no significant correlation was observed inthe number of transplanted islet cells. Subjects that de-veloped portal thrombosis received higher PCV (p < 0.05;

Table 3: Univariate predictors of portal vein thrombosis in allo-geneic islet transplantation

Portal vein thrombosisp-Value

Recipient dataWeight (kg) 0.229BMI (kg/m2) 0.449Standard liver volume (cm3) 0.550Body surface area (m2) 0.975Change in portal venous pressure (mmHg) 0.001∗

Islet cell dataTransplanted islet cells (IE) 0.991Transplanted islet cells/kg (IE/kg) 0.844Packed cell volume (mL) 0.009∗


Kawahara et al.

Figure 4: Comparison between the patients without portal vein thrombosis and those with portal vein thrombosis. The subjectswho developed portal thrombosis (A) had larger packed cell volume and (B) had a significantly increased portal venous pressure, duringthe islet transplant. Each symbol represents an individual case.

Figure 4A) and had a significantly higher change of portalpressure (p < 0.05; Figure 4B) compared to subjects thatdid not develop partial portal thrombosis.

We applied a multivariate analysis in a multiple logistic re-gression model (Table 4). The change in portal venous pres-sure was found to be an independent factor that was sig-nificantly predictive of portal thrombosis (Odds ratio 1.17,p = 0.021).

Selection of cutoff value of PCV and change in portal

venous pressure for the risk of PVT

The ROC curves were constructed to examine the optimalcutoff values both for PCV and for acute change in por-tal pressure. We found that 5 mL of tissue and a portalpressure change of less than 5 mmHg protected againstthrombosis (Figures 5A and B).

Discussion

The strength of this report lies in the large number of percu-taneous intraportal islet transplants carried out at a singleinstitution (268 procedures in 122 patients) with prospec-tive documentation of portal pressure and procedural com-plications, expanding the previous preliminary report fromour group in 26 subjects (18). Both PVT and elevated PCV

Table 4: Multivariable logistic regression of risk of portal veinthrombosis after allogeneic islet transplantation

Oddsratio 95% CI p-Value

Standard liver volume (cm3) 1.08 (0.99, 1.01) 0.603Change in portal venous pressure 1.17 (1.02, 1.32) 0.021∗

(mmHg)Transplanted islet cells (IE) 1.00 (1.00, 1.00) 0.783Transplanted islet cells/kg (IE/kg) 1.00 (0.99, 1.00) 0.778Packed cell volume (mL) 1.08 (0.78, 1.49) 0.634∗p < 0.05.

infused into the portal system have been suggested pre-viously as potential risk factors for PVT in allogeneic islettransplantation. We previously observed an increasing riskfor acutely elevated portal pressures in patients requiringtwo or three infusions (18). Since then, we, along withmost other islet transplant institutions, set limits on thesafe volume of tissue delivered intraportally recommend-ing that this should be maintained below 5 mL and thattherapeutic intraportal and systemic anticoagulation withintravenous heparin should be initiated in the radiologysuite to minimize the risk of thrombosis, standards thatwere set by discussion among leading islet transplant cen-ters in consensus. Therefore, our current report reflectsthe impact of institution of these guidelines and demon-strates that percutaneous intraportal islet transplantationmay be accomplished with exceedingly low risk—an es-sential component if islet transplantation is to be morebroadly and applied earlier in patients with type 1 diabetes.

We acknowledge that the current findings represent amuch more definitive analysis of that previous preliminaryexperience, but importantly emphasize that with attentionboth to islet purity and quality and to therapeutic anti-coagulation in the immediate peritransplant period, bothavoidance of thrombosis and avoidance of intraperitonealbleeding are achievable goals, in the largest experience ofintraportal islet transplants performed at a single centre.This procedure may be regarded as safe and associatedwith minimal complications from the current experience.The only portal thrombosis complication of any major po-tential clinical significance, complete thrombosis of the en-tire portal vein, has never occurred in our series to date.This is an important point from safety perspective.

Specifically, the expanded series to 268 intraportal proce-dures has allowed us to complete in depth multivariateanalyses, the clear finding confirming that acute portal ve-nous pressure rise is a clear risk factor for partial PVT. Thecalculation of ROCs are new to the analysis, confirmingthat cutoff values of PCV and portal venous pressure rise



Figure 5: Receiver operating

characteristic curve assessment

of (A) the packed cell volume (a

cutoff 5.5 mL was selected, pro-

viding sensitivity 50%, speci-

ficity 84.5% and area under the

curve (AUC) 0.667) and (B) por-

tal venous pressure change to

predict portal vein thrombosis

after islet transplantation (a cut-

off 4.5 mmHg was selected, pro-

viding sensitivity 70%, speci-

ficity 73.2% and area under the

curve 0.716).

are meaningful guidelines to other investigators to avoidPVT in islet transplantation. In this study, we have clearlydemonstrated the impact of institution of these guidelinesand that percutaneous intraportal islet transplantation maybe accomplished with exceedingly low risk. The relation-ship between PCV and SLV is also new, not describedpreviously, and further highlights to other investigators theimportance of lowering the set limits of intraportal tissuemass for patients with small livers. This may become es-pecially important in future clinical islet transplantation asand when this procedure is expanded to include childrenwith small livers.

Based on historical reports, it is surprising that the inci-dence of portal thrombosis is not considerably higher inislet autotransplantation where previously several casesof portal thrombosis, variceal bleeding and disseminatedintravascular coagulation were reported, including the oc-casional patient death (9,19–21). Typically, unpurified isletsare infused in the autotransplant setting of chronic pancre-atitis. The introduction of the Ricordi technique for massislet isolation, the use of purified collagenase enzymeslow in endotoxin, the development of standard operatingprocedures and clinical good manufacturing practice, ultraclean room facilities coupled with stringent islet productrelease criteria have all contributed to the substantial re-duction of portal thrombosis and sequelae in clinical isletautotransplantation (2). In contrast to our current findingsin allogeneic islet transplantation, Bucher et al. found noassociation between portal thrombosis and raised intra-portal pressure in their combined experience of both isletautograft and allogeneic transplants, where they limitedthe tissue volume infused to a mean of 13 mL (22). How-ever, in that report although the rate of portal thrombo-sis was low (3.2%), the risk of intraperitoneal hemorrhagewas high (11.3%). Bleeding posttransplantation is now anentirely avoidable complication with intraparenchymal livertract ablation (8). The 6th annual report of the CITR showedthat partial branch-vein occlusions were identified in 2.2%of transplanted patients (23). In our own prospective expe-rience, partial PVT occurred in 3.7% of our 268 proceduresin 122 subjects overall, but the rate has been 0% in the

most recent 4.5 years (in the most recent 101 percuta-neous procedures).

A previous report from an international multicenter trialsuggested that covert and underlying thrombophilic ten-dencies (protein C, S, antithrombin III, factor V Leiden de-ficiencies or presence of antiphospholipid antibodies) maypotentially exacerbate the risk of portal thrombosis afterislet transplantation (24). However, with therapeutic anti-coagulation initiated both intraportally and systemically atthe time of islet infusion, a prolonged period of low molec-ular weight heparin and aspirin and based on the extremelylow risk of this complication in our most recent 4 years ex-perience, it has not been our routine practice to screen forthese abnormalities.

Interestingly, we found that despite partial portal thrombo-sis, there was no detectable loss of islet graft function asmeasured by the SUITO index or insulin requirements. Onemight have anticipated that thrombosis of a major vesselsupplying the islet graft or entrapment of islets within amacroclot would lead to loss of islet mass, but this doesnot seem to have been the case. This observation is lim-ited, however, to just 10 cases and may therefore be un-derpowered.

The calculation of ROC curves in this study corresponds en-tirely with the current recommendations of limiting the isletPCV below 5 mL and limiting the final elevation in portalpressure after islet infusion to less than 5 mmHg. Analysisof the cases of partial portal thrombosis shown in Figure 2demonstrates that most, but not all, cases of partial por-tal thrombosis were associated with transplants outsideof the above limits, and the occasional thrombus, occurreddespite an optimal islet infusion, suggests that there maystill be other factors unaccounted for that could have con-tributed to the thrombosis, including increased tissue fac-tor or monocyte chemoattractant protein expression thatmay trigger a thrombotic and inflammatory reaction (25–28). One report showed that islet surface heparinizationprevented the IBMIR without increasing bleeding risk andit might be useful to prevent portal thrombosis (29).


Kawahara et al.

We recognize that a major limitation to the interpreta-tion of causality in this study is the limited number of 10occurrences of partial portal thrombosis and the fact thatmost of these occurred historically in our series, with noneoccurring in the past 5 years. Although we surmise thatlimiting the intraportal tissue mass and using therapeu-tic anticoagulation is the primary factor protecting againstthis complication, we recognize that substantial changesin islet manufacture, collagenase enzyme and peritrans-plant management have also occurred and clearly mayhave contributed at least in part to the avoidance of por-tal thrombotic complications in our recent series. Thefact that three minor portal thromboses occurred subse-quent to the PCV and full heparinization protocols in 2005,indicates that factors other than tissue volume and anti-coagulation may contribute, but with such a low incidenceand none in the past 5 years, we cannot resolve causalitycompletely. Furthermore, we recognize that the resolutionof the Doppler ultrasound interrogation of the portal venoussystem is operator and hardware and software dependent,and that with improvements in technology and experience,the sensitivity of detection of peripheral portal thrombosiscould increase over era. Nonetheless, detection of main,left, right or peripheral segmental main branches of the por-tal system are readily detectable when present, and theseare the potential clinically relevant thromboses.

Finally, the question may be reasonably asked whetherpartial thrombosis of the intrahepatic portal vein has anyserious clinical sequelae in islet transplantation. The com-plication is clearly iatrogenic and is best avoided, but thisstudy provides reassuring data that partial portal thrombo-sis does not lead to clot propagation and does not progressto complete thrombosis of the entire porto-mesentericsystem, which would clearly have serious clinical conse-quences.

We conclude that excess PCV and a change of portal ve-nous pressure are critical factors for portal thrombosis af-ter intraportal islet transplantation. We recommend PCV <

5 mL and change in portal venous pressure <5 mmHg tomitigate this risk. If the PCV is substantially elevated above5 mL, consideration may be given to further attempts atislet repurification or further prolongation of the cultureperiod, which may result in further differential loss of ex-ocrine tissue and increased tissue purification. If the recip-ient’s portal pressure is substantially elevated at baselineand the measurement is determined to be accurate, thenserious consideration of abandoning the islet infusion pro-cedure must be given, with the possibility of infusing theislet preparation into an alternative recipient. The occur-rence of partial portal thrombosis does not seem to de-grade clinical islet function and has not been associatedwith clinical sequelae of portal hypertension. In patientswith low SLV and especially in children for future consid-eration, more stringent requirements for islet purificationwill be needed, combined with more cautious monitoringof portal pressure that is strongly recommended, and full

anticoagulation should be routinely applied. Portal throm-bosis is a potentially avoidable complication in clinical islettransplantation.

Acknowledgments

This work was supported by a Clinical Centre Grant from the Juvenile Dia-betes Research Foundation and from a National Institutes of Health (NIH)Clinical Islet Transplantation Consortium (CIT) Grant (no data for subjectsenrolled in the CIT Consortium trials are included in this analysis).

Funding Source: T. K. is supported by a Clinical Fellowship Grant fromAlberta Innovates-Healthcare Solutions (AIHS). A.M.J.S. is supported by aSenior Clinical Scholarship from AIHS and through the JDRF and NIH CentreGrants. N.M.K. is supported by a Pfizer–Wyeth grant and the CanadianInstitutes of Health Research. A.M.J.S., P.S. and A.K. are members of theAlberta Diabetes Institute.

Disclosure

The authors of this manuscript have no conflicts of inter-est to disclose as described by the American Journal ofTransplantation.

References

1. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in sevenpatients with type 1 diabetes mellitus using a glucocorticoid-freeimmunosuppressive regimen. N Engl J Med 2000; 343: 230–238.

2. Ricordi C, Strom TB. Clinical islet transplantation: Advances andimmunological challenges. Nat Rev Immunol 2004; 4: 259–268.

3. Hering BJ, Kandaswamy R, Ansite JD, et al. Single-donor,marginal-dose islet transplantation in patients with type 1 dia-betes. JAMA 2005; 293: 830–835.

4. Bellin MD, Kandaswamy R, Parkey J, et al. Prolonged insulin in-dependence after islet allotransplants in recipients with type 1diabetes. Am J Transplant 2008; 8: 2463–2470.

5. Froud T, Yrizarry JM, Alejandro R, Ricordi C. Use of D-STAT toprevent bleeding following percutaneous transhepatic intraportalislet transplantation. Cell Transplant 2004; 13: 55–59.

6. Koh A, Imes S, Kin T, et al. Supplemental islet infusions restoreinsulin independence after graft dysfunction in islet transplant re-cipients. Transplantation 2010; 89: 361–365.

7. Koh A, Senior P, Salam A, et al. Insulin-heparin infusions peri-transplant substantially improve single-donor clinical islet trans-plant success. Transplantation 2010; 89: 465–471.

8. Villiger P, Ryan EA, Owen R, et al. Prevention of bleeding afterislet transplantation: Lessons learned from a multivariate analysisof 132 cases at a single institution. Am J Transplant 2005; 5: 2992–2998.

9. Walsh TJ, Eggleston JC, Cameron JL. Portal hypertension, hepaticinfarction, and liver failure complicating pancreatic islet autotrans-plantation. Surgery 1982; 91: 485–487.

10. Shapiro AM, Lakey JR, Rajotte RV, et al. Portal vein thrombosisafter transplantation of partially purified pancreatic islets in a com-bined human liver/islet allograft. Transplantation 1995; 59: 1060–1063.

11. Goss JA, Soltes G, Goodpastor SE, et al. Pancreatic islet trans-plantation: the radiographic approach. Transplantation 2003; 76:199–203.



12. Owen RJ, Ryan EA, O’Kelly K, et al. Percutaneous transhepaticpancreatic islet cell transplantation in type 1 diabetes mellitusRa-diologic aspects. Radiology 2003; 229: 165–170.

13. Weimar B, Rauber K, Brendel MD, Bretzel RG, Rau WS. Percuta-neous transhepatic catheterization of the portal vein: A combinedCT- and fluoroscopy-guided technique. Cardiovasc Intervent Radiol1999; 22: 342–344.

14. Mosteller RD. Simplified calculation of body-surface area. N EnglJ Med 1987; 317: 1098.

15. Willett WC, Dietz WH, Colditz GA. Guidelines for healthy weight.N Engl J Med 1999; 341: 427–434.

16. Vauthey JN, Abdalla EK, Doherty DA, et al. Body surface area andbody weight predict total liver volume in Western adults. LiverTranspl 2002; 8: 233–240.

17. Matsumoto S, Noguchi H, Hatanaka N, et al. SUITO index forevaluation of efficacy of single donor islet transplantation. CellTransplant 2009; 18: 557–562.

18. Casey JJ, Lakey JR, Ryan EA, et al. Portal venous pressurechanges after sequential clinical islet transplantation. Transplan-tation 2002; 74: 913–915.

19. Cameron JL, Mehigan DG, Broe PJ, Zuidema GD. Distal pancrea-tectomy and islet autotransplantation for chronic pancreatitis. AnnSurg 1981; 193: 312–317.

20. Mehigan DG, Bell WR, Zuidema GD, Eggleston JC, Cameron JL.Disseminated intravascular coagulation and portal hypertensionfollowing pancreatic islet autotransplantation. Ann Surg 1980; 191:287–293.

21. Memsic L, Busuttil RW, Traverso LW. Bleeding esophageal varices

and portal vein thrombosis after pancreatic mixed-cell autotrans-plantation. Surgery 1984; 95: 238–242.

22. Bucher P, Mathe Z, Bosco D, et al. Morbidity associated withintraportal islet transplantation. Transplant Proc 2004; 36: 1119–1120.

23. Report CITR. CITR Annual Report 2009. Available at:https://web.emmes.com/study/isl/reports/reports.htm.

24. Brennan DC, Shannon MB, Koch MJ, Polonsky KS, Desai N,Shapiro J. Portal vein thrombosis complicating islet transplantationin a recipient with the Factor V Leiden mutation. Transplantation2004; 78: 172–173.

25. Moberg L, Johansson H, Lukinius A, et al. Production of tissuefactor by pancreatic islet cells as a trigger of detrimental throm-botic reactions in clinical islet transplantation. Lancet 2002; 360:2039–2045.

26. Johansson U, Olsson A, Gabrielsson S, Nilsson B, Korsgren O.Inflammatory mediators expressed in human islets of Langerhan-sImplications for islet transplantation. Biochem Biophys Res Com-mun 2003; 308: 474–479.

27. Piemonti L, Leone BE, Nano R, et al. Human pancreatic islets pro-duce and secrete MCP-1/CCL2: Relevance in human islet trans-plantation. Diabetes 2002; 51: 55–65.

28. Titus TT,Horton PJ,Badet L,et al. Adverseoutcomeofhuman islet-allogeneic blood interaction. Transplantation 2003; 75: 1317–1322.

29. Cabric S, Sanchez J, Lundgren T, et al. Islet surface heparinizationprevents the instant blood-mediated inflammatory reaction in islettransplantation. Diabetes 2007; 56: 2008–2015.


portal vein thrombosis is a potentially preventable complication in clinical islet transplantation

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