The Impact of Hepatic Artery Thrombosis on the Outcome of Pediatric Living Donor Liver Transplantations

Round 1

Reviewer 1 Report

In brief: the authors analyzed the factors that play role ın developement of hepatıc artery thrombosis. Also theyhave made a comprehensive analysis of the outcomes of HAT. 

1: The language requires significant improvement ,

2: The 140 degrees angle in figure 2 is not understood. This should be explained in detail. Also the paragraph that explains this is not well understood. 

3: In line 219 the authors sate that they used prosthetıc arterıal conduits. This should be explained. what are these prosthetic arterial conduits?

4: Alteplase is the commercial name of the product therefore please provide either the generic name or the company and country of production of the trade mark. 

5: Between lines 218-224, the authors explain the indications for using prosthetic arterial conduits (in three patients). In line 268,  the authors state that they have not chosen surgical revision in patients with early HAT. 2 of these 6 patients were late HAT which is understandable. My question is why didn't you choose to use the prosthetic arterial conduits in the remaining 3 patients (1 with short artery and 2 with inadequate arterial flow). My other questions is; ın one patient reconstruction of the artery in back table was required. This should should be explained in detail. 

 

Author Response

Response to reviewer comments

 

Authors: Marek Stefanowicz, Piotr Kaliciński, Grzegorz Kowalewski, Adam Kowalski, Mateusz Ciopiński, Marek Szymczak, Agnieszka Kwiecińska, Waldemar Patkowski, Krzysztof Zieniewicz,  Ireneusz Grzelak, Diana Kamińska and Hor Ismail

Article Title: The impact of hepatic artery thrombosis on the outcome of pediatric living donor liver transplantations

 

Dear reviewers:

 

I would like to thank you for taking the time to assess our article. We greatly appreciate the thorough and thoughtful comments provided. Your comments significantly improved our manuscript. It has taken us a rather long time to complete the final revision, but we have made sure that each of the reviewer comments was addressed carefully and the paper is revised accordingly.

 

Attached below are detailed responses to the reviewer’s comments. The latter are

shown in black and our responses in red. Please let us know if you still have any questions or concerns about the manuscript. We will be happy to address them in a timely manner.

 

Sincerely,

The authors

 

1: The language requires significant improvement.

The manuscript underwent English revision by a native speaker.

2: The 140 degrees angle in figure 2 is not understood. This should be explained in detail. Also the paragraph that explains this is not well understood. 

Whenever possible, perfusion via microcatheter (4F) introduced across the anastomosis (usually through the gastroduodenal artery or branch of HA) was applied to keep the vessels open during suture placement (Figure 1). We usually begin anastomosis with three angle sutures to keep the anastomosis open and to facilitate placement of the remaining sutures.

3: In line 219 the authors sate that they used prosthetıc arterıal conduits. This should be explained. what are these prosthetic arterial conduits?

An arterial conduit is an effective rescue option in case of low arterial inflow, arterial wall dissection, or inadequate HA length. We used polytetrafluoroethylene (PTFE) conduits because during these LDLT we did not have access to arterial grafts from the living donor or cryopreserved arterial grafts from deceased donors (Fig. 1).

 

Figure 1. Polytetrafluoroethylene (PTFE) arterial conduit between aorta and donor HA during LDLT.

4: Alteplase is the commercial name of the product therefore please provide either the generic name or the company and country of production of the trade mark. 

We changed the name alteplase to recombinant tissue plasminogen r-TPA.

5: Between lines 218-224, the authors explain the indications for using prosthetic arterial conduits (in three patients). In line 268,  the authors state that they have not chosen surgical revision in patients with early HAT. 2 of these 6 patients were late HAT which is understandable. My question is why didn't you choose to use the prosthetic arterial conduits in the remaining 3 patients (1 with short artery and 2 with inadequate arterial flow). My other questions is; ın one patient reconstruction of the artery in back table was required. This should should be explained in detail. 

We explain in detail the description of the patient without attempted surgical revision after HAT:

In six patients (22.2%) who developed HAT, surgical revision was not attempted. Four of them had eHAT. In one case, reconstruction of the hepatic artery was necessary at the back table. This patient had two HA stumps and end-to-side anastomosis of accessory HA to the main HA was performed. This patient developed irreversible HAT six days after LDLT. Surgical revascularization was not performed after HAT due to concomitant sepsis. The patient underwent liver retransplantation due to liver abscess two months after LDLT, and finally died due to MODS. In two patients who developed HAT at one and 13 days after LDLT, HA was already revised during LDLT surgery due to inadequate or lack of flow and surgical revision after HAT was impossible for technical reasons. In one patient, the HA was very short and small (the artery diameter was 1 mm). In this patient during LDLT immediate revision of HA was performed with a Fogarty catheter. The second patient underwent a failed attempt to make a conduit due to intimal dissection of the abdominal aorta at the time of LDLT. HA reanastomosis was performed and the gastroduodenal and splenic arteries were ligated to improve arterial inflow to the liver graft. Recanalization of the HA occurred 56 and four days after HAT diagnosis, respectively, in both patients.

One patient, who developed HAT 13 days after LDLT, was treated with intravenous infusion of r-TPA at a dose of 0.01 to 0.05 mg/kg/h for 7 days. Spontaneous intrahepatic arterial flow recovery was detected 21 days after HAT diagnosis by Doppler ultrasound.

In the remaining two patients, late HAT occurred (38 and 116 days after LDLT), and their graft function was not impaired. One patient was treated with intravenous systemic infusion of r-TPA at a dose of 0.01 to 0.05 mg/kg/h and successful recanalization of the HA was observed after 7 days. In the second patient, spontaneous intrahepatic arterial flow recovery was detected 13 days after HAT diagnosis.

We did not observe bleeding in patients treated with systemic infusion of r-TPA.

 

 

 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments for author File: Comments.docx

Author Response

Response to reviewer comments

 

Authors: Marek Stefanowicz, Piotr Kaliciński, Grzegorz Kowalewski, Adam Kowalski, Mateusz Ciopiński, Marek Szymczak, Agnieszka Kwiecińska, Waldemar Patkowski, Krzysztof Zieniewicz, Ireneusz Grzelak, Diana Kamińska, and Hor Ismail

Article Title: The impact of hepatic artery thrombosis on the outcome of pediatric living donor liver transplantations

 

Dear reviewers:

 

I would like to thank you for taking the time to assess our article. We greatly appreciate the thorough and thoughtful comments provided. Your comments significantly improved our manuscript. It has taken us a rather long time to complete the final revision, but we made sure that each of the reviewers’ comments has been addressed carefully and the paper is revised accordingly.

 

Attached below are detailed responses to the reviewer’s comments. The latter are

shown in black and our responses in red. Please let us know if you still have any questions or concerns about the manuscript. We will be happy to address them in a timely manner.

 

Sincerely,

The authors

• The manuscript underwent English revision by a native speaker.

 

• Line 110-110, the CIT definition is not correct

 

We changed the definition of cold ischemia (CIT) and updated our results accordingly.

CIT is now defined as the time from starting cold perfusion of the graft and removal of the liver from ice to starting vascular anastomosis.

 

• Line 113-114: has to be specified with what kind of ultrasound criteria you used to decide to revise the portal and arterial anastomosis

 

Immediate revision of HA or PV anastomosis was done, usually with introduction of a Fogarty catheter, when no flow was found in HA or PV, when minimal portal flow was detected with absence of flow in part of the lumen, and when the HA resistive index RI=1 with complete absence of the diastolic signal and very low systolic velocity.

 

• Would be interest to have the data if HAT happen more in patient where you revised the artery in the first time

 

We have that data in our study:

The incidence of intraoperative HA revision after reperfusion was significantly higher in the HAT group (p = 0.0019). In the HAT group, arterial revision was performed in six patients (22.2%); reanastomosis was done in two, and graft artery was washed with saline and heparin in three patients. In one case we observed segmental ischemia – probably caused by a segmental artery missed during harvesting. In the non-HAT group, 16 children (4.3%) developed intraoperative HA flow dysfunction. In four patients, reanastomosis was performed, ten patients underwent HA revision with washing the graft artery with saline and heparin. In two cases, segmental liver ischemia was noted.

Graft arterial flow was reestablished in five out of six patients from the HAT group and 14 out of 16 patients from the non-HAT group who underwent surgical revision during transplant surgery.

 

• Why you routinely use heparin in the post operative period? Any literature support? Why FFP only if >3? Any data for this protocol?

 

In our protocol we routinely use low molecular weight heparin (LMWH) in the postoperative period to prevent vascular thrombosis (enoxaparin at a dose of 0.5 to 1 mg/kg twice a day administered for 2 to  3 weeks), followed by acetylsalicylic acid at a dose of 1 mg/kg once a day for six months. Englesbe conducted a survey to establish the best practice in pediatric liver transplantation [1]. In the section about HAT (step 3a, point 8) he described the use of IV dipyridamole and  heparin. Other authors also use IV heparin in their protocol [2]

In our center, we established INR >3 as a limit for administration of single-dose FFP to diminish risk of early postoperative bleeding, when liver graft function is still not fully sufficient. We believe that administration of FFP in the postoperative period in patients with INR < 3 and no signs of bleeding is unnecessary and may increase the risk of thrombotic complications.

 

1. Englesbe, M.Y.; Kelly, B.; Goss, J.; et al. Reducing Pediatric Liver Transplant Complications: A potential roadmap for Transplant Quality Improvement Inititives Within North America. American Journal of Transplantation 2012, 12, 2301-2306,

2.Uchida, Y.; Sakamoto, S.; Egawa, H.; Ogawa, K.; Ogura, Y.; Taira, K.; Kasahara, M.; Uryuhara, K.; Takada, Y.; Kamiyama, Y.; et al. The impact of meticulous management for hepatic artery thrombosis on long-term outcome after pediatric living donor liver transplantation. Clin Transplant 2009, 23, 392-399, doi:10.1111/j.1399-0012.2008.00924.x.

 

 

• Line 137: weakness of the artery. Has to be specified what do you mean by that

 

We evaluated all Doppler ultrasound examinations. In all patients from the HAT group there was no intrahepatic arterial flow in Doppler ultrasound and this was confirmed by Doppler examination during surgery. Our definition of HAT was imprecise, and we have changed it.

 

• A weakness arterial pulse, as my understanding, was sufficient to bring back the patient to OR. Of these, how many patients still have a weak pulse? Do you still consider these patients as HAT? That’s important, because if it only a low arterial flow, its not HAT, and that can bias your results.

 

We observed deterioration of arterial pulse in comparison with previous Doppler examination in some specific clinical situations, e.g., acute rejection or graft compression. But we did not consider these patients as HAT. Careful surveillance with repeated ultrasound examination allowed us to avoid HAT development in these patients. They required different treatment to improve arterial flow. In some cases, e.g., acute rejection, treatment with pulses of steroids could improve flow in HA, in other situations, patients may have needed surgical revision, e.g., graft compression.

 

• Line 150: selected cases. Which cases?

 

In case of stenosis, kinking or angulation of the HA anastomosis, new arterial anastomoses were created after shortening the donor- and recipient-hepatic arteries.

 

• Line 169: explain why you excluded 6 transplant

 

We have retrospectively reviewed only children after primary living donor liver transplantation as a homogenous group without preexisting vascular problems. Therefore we excluded from the study patients receiving living donor grafts at retranspantation. Two of excluded patients received their first transplantation from deceased donors and retransplantation from living donors, and four underwent retransplantation from a living donor after previous LDLT.

 

• How did you consider HAT in case of multiple anastomosis? How do you consider it on the survival? A HAT in only one of the two anastomosis can be different in case of HAT of a single one?

 

In our material, double arterial anastomosis was performed in 36 patients. HAT developed in three of these children (8.3%), which is not significantly different from patients with single HA anastomosis (6.6%) (p = 0.724) We diagnosed HAT in these patients if intrahepatic arterial flow was absent. If it was present even via only one HA, we did not consider it as HAT. We appreciate the reviewer’s suggestion and agree that it is interesting to demonstrate the impact of multiple anastomoses on patient outcomes. We consider making double arterial anastomoses with graft double arteries as very important protection against HAT that may occur in one of these arteries.

 

• What kind of conduit did you use

We used polytetrafluoroethylene (PTFE) conduits because during these LDLT we did not have access to arterial grafts from living donors or cryopreserved arterial grafts from deceased donors (Fig. 1).

Figure 1. Polytetrafluoroethylene (PTFE) arterial conduit between aorta and donor HA during LDLT.

 

• Line 225: flow dysfunction is too generic, has to be explain what do you mean

 

Indications for implantation of the arterial conduit were intimal dissection in the first patient, and inadequate length of the hepatic artery in the second patient. In the third patient, according to the surgical report, the diameter of the graft artery was 3 mm and the patient artery was 1 mm in diameter, and we did not obtain measurable flow after reperfusion, so we decided to make a conduit to the infrarenal aorta with a PTFE graft.

 

• In the discussion: what is the innovation that your work brings in the literature?

 

Hepatic artery thrombosis after LDLT is a very serious and life-threatening complication. The technical problems with creating an anastomosis on 1.5 to 2.5 mm arteries, sometimes multiple ones, are well recognized by pediatric transplant surgeons. In our opinion, sharing our experience, particularly achieved on a relatively large group of transplants, with detailed description of the procedures, protocols and results achieved by our team might add to the discussion on best practices in LDLT. Careful surveillance with repeated ultrasound examination allowed us to avoid HAT development in patients with significant deterioration of intrahepatic arterial flow.

 

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The authors answered to the concerns. Appropriate to pubblication.