Revascularization Strategies in Liver Transplantation

Abstract

Vascular complications following liver transplantation chan jeopardize the liver graft and recipient survival. Aggressive strategies to diagnose and treat these complications may avoid patient and graft loss. With the evolving knowledge and novel therapies, less invasive strategies are gaining importance in the treatment of post liver transplant vascular complications. Portal, hepatic, and arterial thrombosis may be managed with systemic therapies, endovascular approaches, surgical and lastly with retransplantation. The timing between the diagnosis and the directed treatment is paramount for the success. Revascularization by means of interventional radiology plays an important role in the resolution and long-term patency of arterial and venous complications. This chapter will lead the reader into the most up-to-date treatments of post liver transplant vascular complications.

1. Introduction

Liver transplantation (LT) is the last resource for patients with end-stage liver failure. Currently, the excellent posttransplant survival rates shift the attention to improved patient care, quality of life, and diminishing posttransplant complications. LT can be performed with deceased donors or living donors. Also, the liver can be implanted as the hole organ, as in orthotopic liver transplantation (OLT) (Figure 1), or partial liver (left lobe, right lobe, left lateral segment) (Figure 2). Technical variant grafts include partial liver grafts from living donors, split liver, and reduced grafts and have historically been associated with higher risk of posttransplant vascular complications. The indications for LT and the techniques vary according to the age of the recipient, but basically involve a total liver resection with a graft implantation that requires three vascular anastomosis [hepatic vein (HV), portal vein (PV), and hepatic artery (HA)], and a biliary anastomosis. Each of the vascular anastomosis has a potential to suffer thrombosis and/or stenosis. The early diagnosis and intervention will determine the graft and patient survival, since any one of these may be fatal [1, 2].

Figure 1.

Whole-liver transplant with related surgical anastomosis sites. 1= hepatic vein anastomosis using the recipients three hepatic veins and the common stump of the recipient hepatic veins by the piggyback technique; 2 = biliary anastomosis with choledochojejunostomy; 3 = HA reconstruction; and 4 = PV anastomosis [1].

Figure 2.

Living-donor liver transplant, with left lateral liver graft with surgical anastomoses of the hepatic veins by using the piggyback technique (1), hepaticojejunostomy (2), HA reconstruction with two anastomoses (double HA technique) (3), and PV anastomosis (4) [1].

In the following paragraphs, a detailed review of the pathogenesis of each vascular complication and current available treatment options will be presented.

2. Hepatic vein thrombosis/stenosis

2.1 Pathogenesis and diagnosis

Hepatic vein anastomosis can be complicated by the development of stenosis and thrombosis. When venous drainage from the liver is compromised, liver parenchyma gets congested, causing impairment in the liver function, including a sluggish portal flow, and is called hepatic venous outflow obstruction (HVOO). Clinical manifestations of HVOO are nonspecific but may include abnormal liver function, hepatomegaly, ascites, pleural effusion, and lower-extremity edema. If it occurs in the immediate postoperative period, it can cause refractory graft dysfunction from liver congestion and graft loss. The mortality can be as high as 17–24% [3].

The incidence of HVOO after OLT varies from 0.5 to 9.5%. This incidence can be a little higher (3.9–16%) in living donor liver transplantation (LDLT) [4].

Routine Doppler ultrasound (DUS) performed in the immediate posttransplant period can identify signs of HVOO, such as dilated hepatic veins and dampened phasicity (pulsatility index less than 0.45) as lack of transmission of the right atrial waveform into the hepatic veins. In addition, the flow at the anastomosis often shows turbulence [5]. A computed tomography (CT) scan shows better sensitivity (97% vs. 87%) and specificity (86% vs. 68%) than DUS and allows the observation of parenchymal changes such as hypoattenuation during the portal venous phase or the delayed phase, which could suggest venous congestion [6]. The confirmation of this diagnosis is made by hepatic venography and manometry and is defined as stasis of the contrast medium from anastomotic obstruction on venography or a pressure gradient across the stenosis between the distal hepatic vein and the right atrium >5 mmHg. A pressure gradient of >5–6mmHg is widely accepted as the threshold for induction of symptoms [4].

Early complications (<30 days) are thought to be caused by technical factors such as a tight suture line, venous size match, kinking, and compression from a large graft. On the other hand, chronic (>30 days) obstructions are thought to result from fibrosis around the anastomotic site, intimal hyperplasia, twisting, or compression of the anastomosis from a hypertrophic graft [7].

Particular attention to anastomotic techniques is important such as performing a wide triangulated anastomosis, avoiding rotation of graft at the hepatocaval junction, and stabilization of the graft in an anatomical position [8]. Hepatic vein reconstruction is of particular challenge in right lobe grafts, in adult LDLT. Multiple middle hepatic vein tributaries draining the segment 5 vein (V5) are commonly found in donor hepatectomy using conventional modified right lobe grafts, leading to the performance of multiple anastomosis, including the use of vascular grafts to ensure adequate liver parenchymal drainage [4].

2.2 Revascularization and outcomes

Treatment of HVOO depends on the time of presentation and the cause (Figure 3). Most patients can be managed by interventional radiology (IR), performing a balloon angioplasty, with or without stent placement (Figure 4). During the early postoperative period, given the mechanism of HVOO, there is a high chance of restenosis if angioplasty alone is done. Stent is therefore indicated, also because balloon dilatation carries a risk of anastomosis disruption in the first days. Primary stent placement may be an effective treatment modality with an acceptable long-term patency to manage early posttransplant HVOO. Jang et al reported a technical success rate of 96% and 3-year patency rate of 80% in 21 adult LDLT recipients with HVOO treated with IR [4].

Figure 3.

Algorithm for the management of HVOO. HVOO: hepatic venous outflow obstruction; and IR: interventional radiology.

Figure 4.

Hepatic vein stenosis treated with balloon angioplasty. (a) Left hepatic vein stenosis with evidence of collateral veins. (b) Trans-hepatic access and balloon positioning in the stenosis site. (c) Final aspect after balloon dilatation with resolution of collateral veins.

Surgical options should be considered if HVOO is evident at the initial operation, which can be assessed by a transoperative DUS or in the early postoperative period. Surgery is also preferred if there is thrombosis of the hepatic veins because of the high chance of pulmonary embolism with IR treatment [5]. Retransplantation is considered as a last resource, when recanalization fails after these previous attempts.

3. Portal vein thrombosis/stenosis

3.1 Pathogenesis and diagnosis

The incidence of portal vein complications (PVCs) varies according to the recipient (children vs. adult), the LT modality (LDLT vs. OLT), and the preexistence of portal vein thrombosis (PVT). Untreated, it can lead to retransplantation, which happens in almost half of the recipients with PVT [9, 10].

The incidence of PVT after OLT can be up to 3–7%, 4% after LDLT [10], and up to 30% in children [11]. LT in children can present with additional difficulties related to portal vein reconstruction (short vascular stumps, size discrepancy between the donor’s and the recipient’s vascular structures, anastomotic misalignment, stenosis, anastomotic kinks, low portal flow (<7 cm/s), small portal veins (<4 mm), and use of interposition vascular grafts) that can justify the higher incidence of portal vein complications [12].

The diagnosis of PVT can be made by the detection of clinical signs (fever, abdominal pain, intractable ascites, gastrointestinal bleeding, or encephalopathy) and/or laboratory abnormalities (elevated liver enzymes, elevated ammonia levels, and/or thrombocytopenia), or detected during routine posttransplant DUS examination. Some signs present in DUS can indicate a portal vein complication: decreased or absent PV blood flow, acceleration of blood flow at the PV anastomosis, and postanastomotic jet flow. Any of these findings should prompt a CT scan. A decrease in more than 50% in PV diameter in CT scan is a sign of portal vein stenosis (PVS) even though recipient/donor mismatch should always be considered in cases of LDLT and pediatric recipients. PVT appears in the CT scan as the absence of visible lumen at the site of a thrombus [10, 11, 12].

PVT can be classified into four grades according to Yerdel [13]: Grade I: thrombus at main PV affecting less than 50% of the lumen with or without minimal extension into superior mesenteric vein (SMV); Grade II: thrombus at PV affecting more than 50%, including complete thrombosis, with or without minimal extension into the SMV; Grade III: complete PVT plus thrombosis extending to the proximal SMV with patent distal SMV; Grade IV: complete PVT plus complete thrombosis of the SMV (proximal and distal).

3.2 Revascularization and outcomes

Revascularization options for patients with PVT after LT will depend on the extension of the thrombosis and the time of onset/diagnosis. Surgical revision, systemic anticoagulation, catheter-based thrombolytic therapy, balloon angioplasty and stenting, portosystemic shunting compose the usual algorithm. Retransplantation remains as the last resource when everything else has failed [10].

Early complications (from 24 h to 1 week after LT) are usually associated with technical issues and tend to benefit from surgical revision (redo anastomosis, kinking, liver graft repositioning) (Figure 5). However, IR may play an important role as a salvage treatment when surgical revision of PV anastomoses fails. In contrast to early PVCs, late complications (>30 days), as well as grades 2–4 PVT, are associated with less favorable prognoses [11, 14].

Figure 5.

Algorithm for the management of e-PVT. e-PVT: early portal vein thrombosis; LFT: liver function tests; and PV: portal vein.

Patients with grade 1 PVT without liver graft impairment can be treated with full heparinization [unfractioned or low-molecular-weight heparin (LMWH)] and then maintained anticoagulated with warfarin or rivaroxaban for 3–6 months. IR treatment is the first choice for patients with higher grades of PVT (2–4), portal vein occlusion, failed surgical revascularization, or failed recanalization with systemic anticoagulation (Figure 6). Balloon angioplasty with stent placement has high rates of success and low PVT recurrence [10, 11]. The PV access can be made percutaneously (trans-hepatic or trans-splenic) or via mini-laparotomy for a direct catheterization of the portal venous system through ileo-colic or mesenteric venous branches [10].

Figure 6.

Algorithm for the management of late PVC. PVC: portal vein complication; PVS: portal vein stenosis; PVT: portal vein thrombosis; and IR: interventional radiology.

The trans-hepatic approach is usually chosen for the first attempt; however, in patients with chronic PVT, recanalization can be difficult, precluding venoplasty [15]. The ileo-colic approach involves a mini-laparotomy, followed by a catheterization of a venous branch, introduction of a 7 F sheath, and performance of the portography. This approach has advantages in terms of the certainty of portal catheterization [10]. Another option is the trans-splenic access, which is less injurious to the transplanted liver graft (Figure 7) [11].

Figure 7.

Portal vein thrombosis treated with balloon angioplasty and stent. (a) Trans-splenic access and portography; (b) Passage of the guidewire through the site of thrombosis; (c) Balloon dilatation; and (d) Final aspect after stent positioning.

Despite the chosen access, IR protocols for PVT revascularization usually include catheterization, passage of the guidewire through the thrombosed segment, balloon angioplasty, and stent placement (Figure 7). A thrombolysis may be performed in order to facilitate the aspiration of the thrombus. The catheter is placed inside the thrombus and the thrombolytic agent infused. If the first treatment is considered ineffective, the catheter may be left and a continuous infusion of the thrombolytic agent maintained, from a period of 10 days to 30 days [10]. Patients are left anticoagulated after the procedure, at least for 3 months. Sanada et al. recommended the use of a three-agent anticoagulant therapy that combines low-molecular-weight heparin, warfarin, and aspirin for 3 months following balloon dilation for portal vein stenosis (PVS) in pediatric liver transplantation. Recurrence of PVS reduced from 55.6 to 0% in the long-term follow-up [16].

High rate of technical success can be achieved, and recent studies focus on LDLT. In adults, a rate of 80% was achieved with long-term patency in approximately 50–60% of cases [10]. Cavalcante et al reported on pediatric LDLT recipients with chronic PVT who underwent IR with stent placement using a trans-mesenteric approach. The technical success was of 78.6%; and 31.8% developed restenosis/thrombosis and attempted a new dilatation via transhepatic access. Most of the patients (78.5%) had less than 1 year of PVT, with an 81.8% technical success rate in this group, compared with a rate of 66.7% in patients with more than 1 year of PVT [11].

In cases of PVS, balloon angioplasty is considered the first line of treatment and has produced highly successful results (Figure 8). However, 28–50% of these patients may develop recurrent stenosis. There is no minimal time one should wait to perform an angioplasty, even though some groups are concerned about the risk of rupture of the suture. Some cases of PVS induced by chronic PVT are not resolved with balloon angioplasty, because the wall flexibility induces easy expansion and reversion of the PV wall by inflation and deflation of the balloon. Stent placement benefits these cases [10].

Figure 8.

Portal vein stenosis treated with balloon angioplasty. (a) Trans-hepatic access and portography; (b) Passage of the guidewire through the site of stenosis; (c) Balloon dilatation; and (d) Final aspect.

Early detection and treatment of PVS or PVT are paramount to avoid portal vein occlusion. Occluded PV has a low success of stent placement. After 1 year of PVT, chances can be as low as 0% [17]. The treatment of a completely occluded PV is directed to the management of portal hypertension, which includes medical treatment, shunt surgery (portosystemic shunt or meso-Rex shunt), and ultimately, retransplantation (Figure 6) [18].

4. Hepatic artery thrombosis/stenosis

Hepatic artery complications can be classified into thrombosis and stenosis. Acute complications can be represented by early hepatic artery thrombosis (e-HAT), and chronic complications are related to late hepatic artery thrombosis (l-HAT) and hepatic artery stenosis (HAS). Revascularization strategies for these situations include surgical thrombectomy, endovascular thrombectomy, endovascular thrombolysis, systemic anticoagulation, systemic thrombolysis, and endovascular angioplasty and stent placement. The pathogenesis and best treatment modality of each type of complication will be discussed.

4.1 Early hepatic artery thrombosis

e-HAT presents early in the posttransplant course. There is lack of definition in the literature about the post-LT period in which e-HAT should be classified, some assume 14 days, some 30 days, or even as long as 100 days. It can present asymptomatically and be detected with routine posttransplant DUS, but if left untreated can lead to liver failure and retransplantation. e-HAT has been associated with high mortality rate after LT, around 33% [19].

The incidence varies according to the transplant center, the age of the recipient, the transplant modality, and surgical technique. During the initial experience, rates in children reached 42% and 12% in adult recipients. More recently, the combined reported incidence of e-HAT dropped to 4.4%, and to 1–20% in pediatric recipients. Factors such as the surgical learning curve, development of microsurgical techniques, and the routine use of magnifying lenses during arterial anastomosis are responsible for these improvements. The higher incidence reported in children can be in part explained by the smaller vessels, raising the difficulty of the anastomosis. Centers that have adopted microsurgical technique have in fact reported a low incidence of e-HAT, even with partial grafts, as is the case in LDLT [2, 20]. A study by Li et al., in the setting of adult living donor liver transplantation, reported an incidence of 1.8% of HA complications using magnifying loups instead of the microscope [21].

e-HAT can be associated to surgical technique or intraoperative positioning of the hepatic artery (kinking), and when diagnosed in the first 24h after LT, surgical reintervention to check the position of the hepatic artery, check patency, or even redo the anastomosis is the best approach (Figure 9). Other nonsurgical causes of e-HAT include the development of slow arterial flow during an episode of acute rejection, patient hypercoagulability, cytomegalovirus infection, and immunization status, among others. A cytomegalovirus(CMV) recipient/donor mismatch emerged as a concordant risk factor. Patients submitted to a retransplantation are also in an increased risk of e-HAT [19, 20].

Figure 9.

Algorithm for the management of early hepatic artery thrombosis (e-HAT).

Since symptoms are absent during the first hours after e-HAT, routine DUS is paramount to diagnose and immediately treat this complication. Measuring the resistive index is performed as part of the DUS evaluation. A normal resistive index value ranges between 0.60 and 0.80, and values less than 0.50 have been shown to diagnosis HAS or thrombosis with a sensitivity 60% and specificity 77%. Ultrasound can detect up to 90% of all cases of HAT, but false positives can be seen in the setting of hepatic edema, systemic hypotension, or technical aspects limiting the study. CT scan has the advantage of being rapid, not operator-dependent, provides high spatial resolution of small vessels, and gives a superior anatomical overview with the aid of contrast. The combination of absent flow on DUS with confirmation on CT scan is commonly acceptable for the diagnosis of HAT. Other signs such as elevation of liver enzymes, compromise in liver function may be absent, specifically in the setting of LDLT, where the quality of the liver graft masks this alterations [2, 22, 23].

If HAT is unrecognized, the fate of the liver graft will depend on the potential for and the efficiency of developing a collateral arterial circulation and supervening infection within the compromised biliary tree. Untreated, this can progress to liver failure and death [24].

Interventions for e-HAT include urgent revascularization with thrombectomy, vascular anastomosis revision, and thrombolytic drug therapy. Traditionally, the choice was urgent retransplantation or conservative management. Most centers employ a combination of these interventions. There are no randomized controlled data to guide management. Reported studies often lack clear information about graft and patient outcomes and the selection criteria for treatment [24].

Although retransplant has been the first choice of therapy, it is associated with higher morbidity than primary transplant. Surgical options for acute HAT have traditionally included surgical revascularization and open thrombectomy. With major advancements in technology, endovascular management has emerged as a less invasive alternative treatment option.

A revascularization attempt is performed in approximately half of the cases of e-HAT, with a reported success rate of about 50% [20]. Surgical revascularization can be attempted in the first 24h after the diagnosis an e-HAT. Accerman et al performed urgent surgical revascularization in 31 children with diagnosed HAT after LT. Interventions included thrombectomy, with or without fibrinolysis, creation of a new anastomosis and conduit interposition. Success rates were reported in 61% of the cases [25]. Children are more likely than adults to have a successful outcome after early revascularization (61% of adults and 92% of children) [20, 26].

In the study of Pannaro et al., e-HAT required surgical revision in 77% patients and retransplant in 15.4%. Of the patients that required surgical revision, thrombectomy was performed in the majority and few required hepatic artery anastomotic revision. The graft salvage rate for this group was 80% [27].

In case of failed surgical revascularization, thrombolysis can still be pursued, either locally through endovascular therapy or systemically, as recently reported by our group. Systemic alteplase as a rescue therapy salvaged liver grafts in two children with e-HAT [23].

4.2 Late complications—Late HAT and HA stenosis

Late HAT manifesting months or years after surgery may be asymptomatic or have an insidious course characterized by cholangitis, relapsing fever, and bacteremia. The pathognomonic sign of HAT is the development of nonanastomotic/complex biliary stricture, most commonly at the hilum. The formation of bile casts and duct ischemia predispose the patient to recurrent cholangitis and obstructions with the development of biliary abscesses and liver infarction [2, 20, 28].

Some patients presenting l-HAT develop a neovascularized liver. Even though these patients are prone to develop biliary complications, they are treated with repeated bile duct drainage procedures (endoscopic and/or radiological), and the graft salvage rate can reach 100% [27]. Factors influencing the likelihood of spontaneous, effective collateral formation are poorly understood but include the site of the arterial thrombosis (closer to the hilum), the graft type (split/reduced grafts), Roux-en-Y hepaticojejunostomy, multiple arteries, and the timing after LT [24].

HAS is an insidious vascular complication occurring after LT. The most common complication seen in patients with HAS is biliary strictures. HAS usually occurs at or near the anastomosis site as a result of operative technique. The reported HAS rate after LT ranges from 5 to 11% [21].

HAS can be suspected when DUS presents a tardus parvus waveform (defined as a waveform with a resistive index < 0.5 and a systolic acceleration time <0.08 seconds), but has a low positive predictive value and a high false-positive rate. CT scan is indicated to confirm the diagnosis, and arteriography can be used both as a diagnostic and a treatment option [24]. Treatment options for HAS shifted from surgical reintervention to IR balloon angioplasty, with or without stent placement (Figure 10) [27].

Figure 10.

Hepatic artery stenosis treated with balloon angioplasty. (a) Arteriography demonstrating the hepatic artery originating from the superior mesenteric artery and the stenosis (arrow); and (b) Final aspect after balloon dilatation.

Patients treated with a transluminal radiological intervention can expect a patency rate >90% within 5 years. Repeat interventions may be performed in case of HAS recurrence. Angioplasty is useful in treatment of first-time stenosis, with stenting reserved for resistant stenosis [29].

4.3 Endovascular revascularization

HAT has been reported to be successfully treated with multiple endovascular techniques, including transcatheter intra-arterial thrombolysis (IAT), percutaneous transluminal angioplasty (PTA), stenting, or a combination of these [29]. Selective thrombolysis via the hepatic artery, IAT, has several advantages such as small thrombolytic dose, high localized concentration, and little influence on systemic coagulation. It is thought to be safe and effective if the infusion catheter is placed inside the thrombus. Despite its local effect, hemorrhage is the most common complication of IAT.

Urokinase (UK) and alteplase (t-PA) are the most common thrombolytic agents used, with no documented advantage of one over the other. Thrombolytic agents (plasminogen activators) convert plasminogen into plasmin, which further cleaves the fibrin strands within the thrombus, leading to clot dissolution. t-PA is a more potent activator of plasminogen and has higher affinity for fibrin within the clot. Thrombolytic agents can be infused in spaced doses [19] or continuously [30]. The lowest effective dosage and duration have not yet been determined. Dosages can vary from 1 to 3 mg (t-PA) or from 50,000 to 250,000 IU (UK) [31]. Continuous infusion can be maintained for 2–4 days with different dosing regimens, using up to 9 million units of UK [32]. Intra-arterial thrombolysis should be terminated if there is residual thrombus or persistent HAT after 36–48 h of thrombolytic therapy [33]. The estimated success rate of thrombolysis is of 68% [19].

Careful monitoring of coagulation profile and clinical symptoms is necessary during thrombolysis treatment. Fibrinogen levels should be kept above 100 mg/dl [34]; however, there is no evidence to support that fibrinogen levels are predictive of adverse bleeding; as hemorrhagic complications can also occur with values above 100 mg/dl. If adverse bleeding occurs, thrombolytic agent should be immediately terminated, and any other cause for bleeding should be addressed.

IAT can reveal other reasons for HAT, including kinking, anastomotic stenosis, or stricture, which if left untreated can lead to rethrombosis. The combined use of thrombolysis with PTA and/or stenting has been shown to have better patency and survival rates than thrombolysis alone. Angioplasty is useful in treatment of first-time stenosis, with stenting reserved for resistant stenosis [35].

4.4 Systemic thrombolysis

Medical management without surgical or endovascular intervention has yet to be confirmed as an effective treatment option for HAT. Our group recently published the successful outcome with the multimodal treatment for e-HAT after pediatric LT. Two children were successfully rescued with systemic t-PA and heparinization [23].

Posttransplant anticoagulation, even with LMWH as part of the protocol, has been shown to reduce the incidence of HAT, but does not lead to resolution (31, 32). Our posttransplant protocol includes prophylactic heparin when TTPA < 2.5 times control, and aspirin 3mg/kg when the patient resumes oral intake and platelets are >100.000. DUS is performed during the LT, in the first 24h after the transplant, and subsequently according to clinical judgment.

Systemic heparinization can salvage a liver graft after HAT if the patient has a neovascularized liver or if there is HA recanalization, which occurs less frequently. The complete understanding of how systemic heparinization or systemic thrombolysis can actually prevent retransplantation is still under debate [23, 27]. However, it is a valuable salvage therapy for these patients, and one should not hesitate in administering even if the patients go to a retransplant waiting list.

5. Conclusions

Posttransplant vascular complications jeopardize the liver graft and can impact on graft and patient survival. An impeccable surgical technique, along with close posttransplant surveillance to ensure an early diagnosis and prompt treatment, will enhance the chances to avoid retransplantation. It was not until recently that IR and thrombolysis have replaced retransplantation as the first treatment choice. Complications occurring <24 h after the LT are still best managed with surgical revision, because technical issues are usually responsible and can be addressed. Later occurring complications, however, are best managed nonoperatively, with high success rates for current therapies. Retransplantation is reserved as last resource when previous attempts have failed or when the liver grafts are already beyond salvation.

Acknowledgments

This article was funded by Teaching and Research Institute of Hospital Santa Casa de Porto Alegre, Porto Alegre, Brazil.