Venous thromboembolism following lung transplantation

Abstract

Lung transplantation (LT) is currently a surgical therapy option for end-stage lung disease. Venous thromboembolism (VTE), which can occur after LT, is associated with significant morbidity and mortality. Because of improved outcomes, increasing numbers of patients are receiving LT as treatment. Patients on the waitlist for LT tend to be older with weakness and frailty in addition to pulmonary symptoms. These factors contribute to a heightened risk of postoperative VTE. Furthermore, patients who clinically deteriorate while on the waitlist may require extra corporeal membrane oxygenation as a bridge to LT. Bleeding and thromboembolism are common in these patients. Pulmonary embolism (PE) in a freshly transplanted lung can have significant effects leading to morbidity and mortality. PE typically leads to impairment of gas exchange and right ventricular strain. In LT, PE can affect healing of bronchial anastomosis and may even contribute to the development of chronic allograft lung dysfunction. This article discussed the incidence, clinical features and diagnosis of VTE after LT. Furthermore, the treatment modalities, complications, and outcomes of VTE were reviewed.

Key Words: Lung transplantation; Venous thromboembolism; Pulmonary embolism; Pulmonary infarction; Deep vein thrombosis; Airway complications; Bronchial ischemia; Chronic lung allograft dysfunction; Extracorporeal membrane oxygenation; Anticoagulation

Core Tip: The incidence of venous thromboembolism after lung transplantation (LT) contributes to morbidity and mortality. Due to the loss of dual blood supply after LT, a hypoxic milieu exists in the bronchial mucosa of the transplanted lung. Due to the tenuous blood supply, any embolism to the transplanted lung can worsen the hypoxia. This leads to ischemia of the bronchial wall and airway complications. Persistent hypoxia often leads to fibrosis and may contribute to the development of chronic lung allograft dysfunction. Since venous thromboembolism following LT is often asymptomatic, routine screening would be beneficial to patients.

INTRODUCTION

Lung transplantation (LT) is currently a surgical option to treat patients with end-stage lung disease. Advancements in surgical techniques, diagnostic methods and treatment of rejection, the improved methods of donor organ preservation, and the better understanding of the pathophysiology of various aspects of LT have all contributed to improved outcomes. However, the incidence of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), poses a threat to patient outcomes following LT. We reviewed the incidence, risk factors, and diagnosis of VTE after LT as well as prophylactic and therapeutic measures. The effects of VTE after LT on survival were also reviewed.

Globally, VTE contributes significantly to the mortality and morbidity in the general population. It affects 10 million people worldwide every year[1]. The global mortality rate due to VTE ranges from 9.4%-32.0%[2]. Of the 650000 patients diagnosed with PE every year, about 200000 of those patients die[3]. In the United States, 1200000 cases of VTE occur annually, out of which 370000 cases are PE. In Europe, 296000 cases of PE are estimated to occur every year[4]. Globally, the reported incidence of VTE is likely underestimated. Against this background, it becomes apparent that VTE and PE are a detrimental risk to a transplanted lung. Both VTE and PE can be asymptomatic and are often undiagnosed after LT. The first case series of patients with VTE after LT was first published only in 1995[5].

HISTORICAL ASPECTS OF VTE AND LT

VTE

In the 18^th century, the first descriptions of clots in pulmonary arteries were made by Morgagni, Laennec, and Cruveilier[3]. In 1858, Virchow described an embolism to the pulmonary artery via the inferior vena cava and postulated the causes for thrombosis. This is known as Virchow’s triad and is comprised of stasis, vessel injury, and hypercoagulability. McFadden and Ochsner[3] described the history and treatment of VTE thromboembolism while crediting the term “embolism” to Virchow.

It is noteworthy that the initial attempts of PE treatment were surgical. In 1872, Trendelenburg recognized the sudden critical aspects of this condition and tested various surgical treatments on experimental animals. He developed the pulmonary embolectomy technique, which now carries his name. While his patients did not survive the procedure, his pupil Kirschner reported the first successful case of embolectomy for PE in 1924. Under controlled conditions of cardiopulmonary bypass (CPB), Cooley attempted embolectomy in 1961. One year later, the first successful case of pulmonary embolectomy using CPB was reported by Sharp. Anticoagulants can also be a therapeutic option. As a second-year medical student, MacLean accidently discovered heparin, with its clinical use later described by David Murray. The discovery and use of oral anticoagulants occurred in the 1940s. Caval interruption by surgery, clips, or filters was described as another therapeutic option.

LT

After many years of experimental work by several researchers, the first report of LT in humans was published in 1963 by Hardy et al[6]. However, the patient did not survive long. Further attempts at LT in the United States and Europe were unsuccessful and discouraging. It took 20 more years for LT to emerge as a possible surgical option. In 1989, Cooper[7] reported the first successful case of LT. Following this report, LT gradually became accepted as a surgical therapy in appropriate patients with end-stage lung disease. Currently, 4600 LTs are performed worldwide[8].

PATHOPHYSIOLOGICAL ASPECTS OF LT IMPACTING PE

Dual circulation in the normal lung

The lungs have a dual blood supply comprised of pulmonary arteries and bronchial arteries. The pulmonary artery transports the entire venous return of the body with deoxygenated blood to the alveoli for oxygenation and the oxygenated blood returns to the left atrium via the pulmonary veins for subsequent distribution to the rest of the body. The bronchial arteries supply oxygenated blood to the major airways and subdivisions to the respiratory bronchioles, lung tissue, and visceral pleura. The nourishment and efficient functioning of the major airways to small airways, lung tissue, and visceral pleura depend on antegrade flow in the bronchial arteries carrying oxygenated blood. The bronchial veins have two venous plexuses including the superficial that drains into the azygous vein or the right atrium and the deep intralobar bronchial veins that drain into the pulmonary veins thereby causing an insignificant shunt.

The bronchial circulation, in addition to supplying oxygen and nutrients, has other vital functions. It plays a role in the formation of the bronchial lining fluid, in the formation of lymphatic fluid and flow, in muco-ciliary function and clearance of particles[9], and in regulating blood flow to maintain the mucosal humidity and temperature[10]. The intrapulmonary and bronchial vascular plexuses open when either the pulmonary arterial or bronchial arterial supply is reduced or interrupted. In cases where there is long-standing significant hypoxia, the bronchial arterial supply increases. Marchand et al[11] described the bronchial arterial variations in health and disease. The microscopic anatomy of bronchial arteries, collateral vessels, and sphincters for these variations have been described in an excellent review by Pump[12].

Changes in bronchial circulation following LT

During LT, only the pulmonary arteries and pulmonary veins are anastomosed. The bronchial blood supply to the allograft is not re-established. In such cases, the blood supply to the major airways and lung tissue of the allograft is mainly by retrograde flow in the bronchial arteries through the vascular plexus between the pulmonary and bronchial arterial anastomosis. This retrograde bronchial flow transports deoxygenated blood at a much lower pressure with resultant mucosal hypoxia of the allograft. Direct measurement of airway tissue saturations during surveillance bronchoscopies revealed significantly low tissue saturations in the allograft even in the presence of normally healing bronchial anastomosis[13].

Pathophysiological effects of altered bronchial microcirculation after LT

Ischemia with consequent hypoxia is known to be a precursor for inflammation and repair by fibrosis. Similar changes occur in the bronchial mucosa too. Autopsy studies by Luckraz et al[14] of lung allograft specimens from 99 patients revealed that a significant loss of microvasculature preceded the development of obliterative bronchiolitis, thereby suggesting a possible role of ischemia in the development of fibrosis[13]. Thus, it could be one of the factors leading to development of chronic lung allograft dysfunction (CLAD)[15]. Anastomotic complications such as dehiscence or stenosis can occur due to allograft mucosal ischemia as well.

Role of bronchial artery revascularization

To mitigate the untoward effects of altered microcirculation and bronchial mucosal hypoxia in the allograft, bronchial artery revascularization (BAR) has been performed in a few centers. The proponents of BAR claim excellent outcomes in bronchial anastomotic healing and a reduced incidence of CLAD[16]. The benefits and limitations of BAR are still a matter of debate and fall beyond the scope of this manuscript. It should be noted that most centers do not routinely perform BAR due to the complexity of both donor and recipient operations.

DELETERIOUS EFFECTS OF PE AFTER LT

Following interruption of bronchial circulation, the lung allograft is in a state of ischemia and is dependent solely on the pulmonary circulation for gaseous exchange and nutrition of the airways and lung tissue. Thus, it is logical to note that the effect of PE depends on the size and load of the offending embolus. Major embolus can lead to pulmonary infarction, while smaller ones can lead to ischemic anastomotic complications. Over time fibrosis of small airways can contribute to the development of CLAD[15].

LITERATURE SEARCH

We used the keywords “venous thromboembolism”, “pulmonary embolism”, “deep vein thrombosis”, “lung transplantation”, and “survival” to search the PubMed, Embase, and Ovid databases. Furthermore, we chose not to limit the searches within a time frame because LT is a relatively recent surgical procedure and has only been practiced widely in the last three decades. We identified one prospective study (2023), sixteen retrospective studies, and one nested case control study (2007) on VTE following LT. We also identified one systematic review and one case report on PE after LT.

CLINICAL DATA ON VTE FOLLOWING LT

Fifteen retrospective studies were reviewed and are described below. Three tables depict data from retrospective studies only, grouped in three different time periods based on year of publication. The publications representing prospective study, systematic review, nested case-control study, case report, and the remaining retrospective studies were not tabulated and are discussed in the text. Besides the systematic review and retrospective nation-wide multicenter study, all studies were single-center studies. Table 1 shows data from six retrospective studies published from 2021 to 2024. Four of the studies[17-20] analyzed VTE following LT. The study by Magin et al[15] analyzed the incidence of CLAD after VTE in LT patients, and Moneke et al[21] studied both arterial and VTE after LT. Table 2 shows the tabulated data of four retrospective studies[20,22-24] on VTE following LT, which were published in 2019 and 2020. Table 3 tabulates data from five retrospective studies on VTE following LT published from 2015 to 2018, including one nation-wide multicenter study consisting of 16513 patients and four single-center studies[25]. Of the 4 single-center studies, Sáez-Giménez et al[26] studied the effects of extended 90-day prophylaxis with enoxaparin, while the other three studies looked at VTE after LT[27-29].

Table 1 Retrospective studies published during 2021-2024 on venous thromboembolism following lung transplantation.

Ref.	LT patients, n	VTE, n (%)	PE/infarct, n (%)	DVT, n (%)	Risk factors	Survival	Remarks
Ruigrok et al[17], 2024	253	45 (18)	27 (60)	18 (40)	Long ICU stay, retransplant	No effect	UL DVT: 13 (29); LL DVT: 5 (11)
Walter et al[18], 2024	114	41 (35)	18 (44)	23 (56)	Age, CF, ECMO, in hospital pre-LT	No effect	UL DVT: 12 (30); LL DVT: 11 (26)
Magin et al[15], 2024	828	NA	57 (6)	NA	NA	NA	High risk of CLAD
Moneke et al[21], 2023	221	74 (33)	34 (15)	NA	Age > 55 year, BMI > 25	Low 1-year survival	NA
Kanade et al[19], 2021	324	97 (30)	NA	NA	Female, central line > 3 days, in hospital pre-LT	No effect	NA
Zheng et al[20], 2021	235	58 (25)	8 (13)	44 (76)	CPB, interrupting thromboprophylaxis	NA	Routine screening picked up more cases

LT: Lung transplantation; VTE: Venous thromboembolism; PE: Pulmonary embolism; DVT: Deep vein thrombosis; ICU: Intensive care unit; UL: Upper limb; LL: Lower limb; CF: Cystic fibrosis; ECMO: Extracorporeal membrane oxygenation; NA: Not available; CLAD: Chronic allograft lung dysfunction; BMI: Body mass index; CPB: Cardiopulmonary bypass.

Table 2 Retrospective studies published during 2019-2020 on venous thromboembolism following lung transplantation, n (%).

Ref.	Study groups	LT patients	VTE	PE/infarct	DVT	Risk factors	Survival	Remarks
Zheng et al[22], 2020	SLT: 143; DLT: 78	197	47 (23)	NA	NA	Prophylaxis interruption	NA	UL DVT: 55% and VTE 70% in 30 days
Jorge et al[23], 2020	Group I (2005-2008): No DVT screening. Group II (2008-2014): DVT screening	NA	NA	NA	NA	High cholesterol had 6.9 times risk of DVT	Better survival in group II due to routine screening	NA
Zhao et al[31], 2019	SLT: 78; DLT: 46	124	32 (26)	4 (3)	30 (97)	ECMO	NA	2 patients had both PE and DVT. No effect due to PICC
Fan et al[24], 2019	NA	316	19 (6)	NA	NA	Age, SLT, long ICU stay	NA	VTE much higher without prophylaxis

LT: Lung transplantation; VTE: Venous thromboembolism; PE: Pulmonary embolism; DVT: Deep vein thrombosis; SLT: Single lung transplantation; DLT: Double lung transplantation; NA: Not available; UL: Upper limb; ECMO: Extracorporeal membrane oxygenation; PICC: Peripherally inserted central catheter; ICU: Intensive care unit.

Table 3 Retrospective studies published during 2015-2018 on venous thromboembolism following lung transplantation, n (%).

Ref.	LT	VTE	PE/infarct	DVT	Time to VTE, median (IQR)	Risk factors	Survival	Remarks
Ribeiro Neto et al[27], 2018	701	300 (49)	33 (5)	300 (43), UL: 71%	20 (9-82) days	Male, ECMO, long ICU stay	Reduced in UL and BK DVT	High incidence after screening
Aboagye et al[25], 2018	16318	1029 (6)	175 (1)	854 (5)	NA	Male, age > 65, ventilation > 96 hours	NA	3.4 times higher risk of death with PE
Larios et al[28], 2018	74	31 (42)	2 (6)	24 (32)	NA	NA	No effect	Both PE and DVT 5 (16)
Sáez-Giménez et al[26], 2017	333	35	29	NA	40 (14-112) days	Male sex, ILD	NA	Extended 90 days prophylaxis did not prevent VTE
Evans et al[29], 2015	117	NA	18 (15)	98	NA	NA	SLT, CPB, and DVT-LL all lower survival	UL: 45 (39); LL: 53 (45)

LT: Lung transplantation; VTE: Venous thromboembolism; PE: Pulmonary embolism; DVT: Deep vein thrombosis; IQR: Interquartile range; ECMO: Extracorporeal membrane oxygenation; ICU: Intensive care unit; UL: Upper limb; BK: Below knee; NA: Not available; ILD: Interstitial lung disease; SLT: Single lung transplantation; CPB: Cardiopulmonary bypass; LL: Lower limb.

Incidence of VTE following LT

We included both PE and DVT occurring in the upper limbs (ULs) and lower limbs (LLs) when we refer to VTE. We also included thrombosis in other peripheral veins such as retinal vein thrombosis. In the only prospective study of VTE in LT, Marshall et al[30] analyzed the effects of three different protocols of VTE prophylaxis and reported VTE occurring in 28.8%-38.5% of LT patients. Among the DVTs, the site was most often in the UL and related to vascular indwelling catheters. Overall, the reported incidence of VTE ranged from 6%-45% following LT (Tables 1-3). In order to avoid overlap, the nation-wide multicenter study and the study by Zheng et al[22] were excluded. Thirteen retrospective studies remained including 4881 LT patients. VTE occurred in 852 patients with an incidence of 17%. These studies were comparable in the primary diagnosis of VTE, which was reported in LT patients across studies. Ten out of these retrospective studies reported PE in addition to VTE. There were 230 cases of PE out of a total of 3100 patients with a 7.4% incidence of PE after LT.

Four studies reported VTE, PE, and combined PE with DVT[20,26,28,31]. Out of a total of 766 patients, 43 patients (5.6%) were diagnosed with PE, and 19 patients (2.5%) were diagnosed with a combination of PE and DVT. Only the study by Sáez-Giménez et al[26] analyzing 333 LT patients reported pulmonary infarction in 6 patients (1.8%) out of the 35 patients (10.5%) with PE. Five retrospective studies provided additional data on the site of DVT[17,18,22,27,29]. Out of 1382 patients receiving an LT in these 4 studies, 439 (31.7%) had DVT including 311 (70%) in the UL and 161 (30%) in the LL. It is interesting to note that in the nation-wide multicenter study by Aboagye et al[25], the incidence of VTE was quite low [VTE: 1029 patients (6.3%); PE: 175 patients (1.1%)].

Furthermore, there appears to be no significant change in the incidence of VTE over the past 10 years. Among the studies reported from 2021 to 2024, VTE occurred in 15.1% of patients, and PE occurred in 6.9% of patients. For the cases reported in 2019 and 2020, VTE occurred in 13.4% of patients and PE in 3.2% of patients. For the cases reported from 2015 to 2018, VTE occurred in 30.4% of patients and PE in 6.1% of patients (Table 4). It is noteworthy that the incidence of PE has remained the same over this 10-year period. A systematic review of 12 studies reported a 4% incidence of PE following LT[32], which is similar to the incidence of PE as reported in the retrospective studies.

Table 4 Calculated incidence of overall venous thromboembolism (deep vein thrombosis and pulmonary embolism) and pulmonary embolism alone following lung transplantation.

Period of publication of the studies	Number of studies	Incidence of overall VTE (DVT + PE)	Incidence of PE alone
2021-2024	6	15.1%	6.9%
2019-2020	3	13.4%	3.2%
2015-2018	3	30.4%	6.1%

VTE: Venous thromboembolism; DVT: Deep vein thrombosis; PE: Pulmonary embolism.

Clinical risk factors for the development of VTE

Eleven of the retrospective studies identified clinical risk factors for the development of VTE after LT. These important risk factors for developing VTE after LT included older age (> 55 years)[18,21,24,25,33], male sex[25-27], use of extracorporeal membrane oxygenation (ECMO)[18,22,27], and prolonged intensive care unit (ICU) stay[17,24,27]. However, two studies reported female sex as a risk factor[19,34]. Two studies stated that the primary disease indicating LT was idiopathic pulmonary fibrosis (IPF) and was an independent risk factor[35,36]. Other studies reported cystic fibrosis[18] and interstitial lung disease[26] as risk factors. It is interesting to note that patients with hypercholesterolemia showed a 6.9 times higher risk of DVT in one study[23]. Obesity[35], body mass index > 25[21], and diabetes mellitus[33] have also been reported as risk factors. Use of the immunosuppressive drug sirolimus has been reported to cause VTE[37,38].

Effects on survival

PE has a negative effect on survival after LT. Following PE diagnosis, the 1-year survival after LT is only 50%-59%[5,21,39]. Following PE, the odds ratio of death is 3.4 in patients after LT when compared to patients with no VTE[25]. Deaths due to PE occur within the first year after LT. Among these, 80% of these deaths occur in the first month following LT[32]. While DVT has no impact on survival after LT[17-19,28], two studies[27,29] reported lower survival for patients with DVT. Jorge et al[23] reported improved survival after routine screening for DVT after LT.

Time to first occurrence of VTE

Across the 20 studies identified by our search strategy, the median time to a VTE event after LT ranged from 9-179 days. Eight retrospective studies reported the median time to the first VTE incident following LT. Among these, four studies involving 1156 LT patients reported a median time of 7-23 days[20,27,30,31]. These studies were recently published (2018 to 2023). In the other four studies involving 679 LT patients, the median time to VTE ranged from 40-175 days[26,33,34,36]. It is noteworthy that these studies were published from 2003 to 2007, excluding one study[26]. Better screening methods and diagnostic protocols for VTE in recent years are the reasons for this difference in time to event.

DISCUSSION

This discussion pertains primarily to the effects of PE after LT, although some references to VTE may be made. To enable an easy narrative, a chronological order is maintained, while the discussion proceeds along preoperative, intraoperative, and postoperative periods.

Preoperative period

Patients who are on the waitlist for LT are limited in their activities due to underlying primary lung disease. With an increasing number of LT performed in older patients, the incidence of frailty also increases[40]. Preoperative frailty with decreased mobilization contributes to a milieu conducive for VTE even prior to LT. Diabetes mellitus can lead to a thrombogenic state with a two-fold increase in VTE. There is a higher risk of developing PE compared to DVT[41]. Diabetes mellitus also inhibits fibrinolysis due to elevated levels of plasminogen activator inhibitor 1, leading to a thrombogenic state[33]. Among the diseases for which LT is indicated, IPF has been reported to be prothrombogenic[42,43]. Among patients with VTE, there was a higher risk of IPF[44]. A large population-based study in the United Kingdom[45] demonstrated that patients with IPF had a 4-fold higher chance of a prothrombotic state and a 3-fold higher chance of death. Nathan et al[36] identified 23 of 72 patients receiving LT with IPF. In that study, all 6 patients with PE also had IPF. No other diseases were found to increase the development of PE. Patients awaiting LT on anticoagulants pose unique challenges. Reversal of anticoagulation is often inadequate given the lack of notice to adequately stop the oral anticoagulants. An excellent study by Shepherd et al[46] analyzed reversal of preoperative anticoagulants prior to LT. Interestingly, they noted much higher thrombotic complications than bleeding in this cohort of patients.

Patients awaiting LT may deteriorate and require “bridging” with either mechanical ventilation or ECMO until LT[47,48]. Despite the use of anticoagulants during ECMO support, the risk of thrombosis still exists[49]. A systematic review on VTE during ECMO support[50] analyzed 30 studies and reported a VTE incidence of 40%-46%. A similarly high incidence of DVT (53%) after ECMO was reported in another systematic review of 18 studies[51]. The authors recommended routine screening for DVT following removal of the ECMO cannula and separation from ECMO. In Zhao et al’s review, 124 patients who received LT, identified 32 patients who developed VTE[31]. They noted that ECMO was used in 90.6% of patients with VTE compared to the use of ECMO in 69% of patients without VTE, suggesting a higher incidence of VTE after ECMO.

Two risk factors of VTE in patients awaiting LT are the degree of frailty and oxygen requirements. Prophylactic measures to reduce these risks can be undertaken. The degree of oxygen supplementation needed by patients awaiting LT ranges from low levels that can be provided by portable oxygen cylinders to higher levels that may require either high flow nasal cannula, mechanical ventilation, or even ECMO. Ambulatory patients can undergo graded physical therapy. Bedridden patients due to frailty with a need for mechanical ventilation or ECMO are at an even higher risk of VTE due to immobilization. In patients awaiting LT, prophylactic measures to prevent postoperative VTE include the following: (1) Graded physical activity to the greatest extent possible. Active and passive limb physiotherapy either manually or with the use of specialized devices, such as Letto machines or sequential compression devices, to prevent DVT is important; (2) Adequate hydration must be maintained because dehydration predisposes patients to VTE; (3) Pharmacologic thromboprophylaxis using either subcutaneous low molecular weight heparin or oral anticoagulants should be considered in high-risk patients. The risks of bleeding should be weighed against the benefits of preventing VTE; and (4) There must be a high index of suspicion and low threshold to look for DVT/PE in patients in the ICU, and patients should be treated aggressively.

Intraoperative period

Intraoperative mechanisms of VTE during LT and preventive measures: Thrombus can occur at the site of pulmonary artery anastomosis during LT and cause PE later. Meticulous surgical techniques ensuring endothelium to endothelium apposition of the pulmonary arteries is mandatory to prevent anastomotic site thrombus formation. To this end, care must be taken to avoid adventitial or subendothelial tissue in the anastomosis that might be the nidus for formation of thrombus at the anastomotic site. For patients on ECMO before LT, ECMO support is weaned after implantation of the lungs before the ECMO cannula are removed. Dislodgement of preexisting DVT due to long-standing ECMO cannula can cause VTE[49]. Following removal of the cannula, the cannulation site is allowed to bleed by exerting proximal pressure in the vein. This procedure allows the escape of clots if present and prevents PE.

Choice of extracorporeal support during LT: The use of CPB has been associated with an increased incidence of VTE[20,34]. The prothrombotic state exists for 1 month after the use of CPB. This perioperative prothrombotic state exists for 1 month even after avoidance of CPB[52]. This explains the high incidence of VTE in the first month after LT. Elevated levels of clotting factors in patients with VTE after LT have been reported[53,54]. Patients who undergo LT “off-pump” without CPB or ECMO support also have a hypercoagulable state[55]. Intraoperative ECMO has been shown by many studies[47] to be more beneficial than CPB during LT and could be used preferentially instead of CPB during LT.

Intraoperative management of patients on anticoagulants prior to LT: Paradoxically, the incidence of thrombotic complications is higher than bleeding during LT in patients already on anticoagulants. Shepherd et al[46] provided an algorithm on the methods to reverse anticoagulation in patients taking oral anticoagulants prior to LT. Delaying LT to the daytime and allowing time for reversal has been suggested. Avoiding nighttime LT is beneficial[56]. Reversal is typically completed by transfusion of fresh frozen plasma, prothrombin complex concentrates[57], or administration of vitamin K. The method chosen is based on the condition of the recipient. Renner et al[58] described perioperative management of patients who received LT and were previously on rivaroxaban.

Use of donor lungs with pulmonary embolus: Researchers demonstrated good outcomes following LT using donor lungs with fulminant PE with no adverse effect on survival and an improved 5-year CLAD-free survival in these patients[59,60]. The use of donor lungs after thrombolysis and thrombectomy have also been described[61,62]. However, Terada et al[63], who analyzed 22 donor lungs with PE, suggested that caution should be exercised prior to accepting donor lungs with PE because of the higher incidence of acute cellular rejection (45%) and CLAD.

Type of LT and the impact on postoperative PE: PE occurs most often in patients undergoing a single LT (SLT)[24,35] when compared to patients undergoing a double LT. The incidence of PE in combined heart-LT (HLT) cases is the lowest. An excellent autopsy study by Burns and Iacono[64] on patients who died following LT confirmed that PE is an under-recognized entity with the lowest risk in HLT patients (2.9%), followed by double LT patients (20.6%) and with the highest risk (76.5%) in SLT patients. Noting the higher incidence of PE in an LT only, they proposed that the presence of an arterial anastomotic suture line in LT could be a thrombogenic site because there is no pulmonary arterial anastomosis in HLT. In SLT, they suggested that the increased incidence PE in the allograft when compared to the native lung was due to increased and preferential flow to the allograft. The pulmonary vascular resistance is higher in the native lung and results in preferential flow to the allograft. Therefore, a greater likelihood of any embolus travelling to the transplanted single lung exists.

Postoperative period

Thromboprophylaxis: Conflicting evidence exists in the literature regarding efficacy of prophylaxis after LT. A prospective study by Marshall et al[30] reported a high incidence of VTE after LT despite aggressive prophylaxis with enoxaparin. Similarly, Sáez-Giménez et al[26] reported a failure to reduce VTE despite 90-day extended prophylaxis with enoxaparin. Some authors reported a reduction of VTE incidence of 1.5% with prophylaxis compared to 15% incidence of VTE without prophylaxis[24]. Interruption of thromboprophylaxis within the first 5 days was reported to be a risk factor for the development of VTE with an odds ratio of 4.12[22]. The common reasons for interruption of thromboprophylaxis is thrombocytopenia due to infection or drugs. Extended (30 days) enoxaparin use as a prophylactic drug reduced the incidence of VTE to 0% compared to a 26% incidence of VTE in the routine prophylaxis group[65].

Screening protocols: Since VTE can be asymptomatic, screening is valuable in identifying patients with VTE so timely therapy can commence. Zheng et al[20] described “routine” duplex scanning of all LT patients in the first 2 weeks after surgery and when clinically indicated thereafter. Of the 40 patients diagnosed with VTE in the first month, 30 patients were detected solely due to screening. Sáez-Giménez et al[26] reported a series of patients who were screened using a “routine” ventilation-perfusion scan immediately prior to discharge. Jorge et al[23] reported a large series of patients over two periods. No DVT screening was performed during the first period prior to 2008. In the second period after 2008, all patients were screened on day 0 and day 14 after LT. They observed an improved 1-year survival among the screened patients.

Postoperative rehabilitation and preventive measures: Once the bleeding settles with minimal drainage in the chest tubes after LT and after separation from the ventilator, early mobilization is recommended. Prompt and early removal of monitoring and central lines help in early mobilization. Pharmacological measures of prophylaxis must be considered. In patients with a high bleeding risk, mechanical prophylaxis such as compression stockings or sequential compression devices will be beneficial.

Clinical presentation and diagnosis of VTE after LT: The clinical presentation depends on the site and size of the blood clots. The reported incidence has been shown to be underestimated because routine screening detects more cases of VTE that are either asymptomatic or detected while screening other issues[20]. VTE could either be DVT involving the UL or LL, or PE. Both conditions have the same risk factors and similar pathogenetic mechanisms involving a hypercoagulable state, endothelial damage, and stasis of blood flow. The site of involvement is different, with DVT involving the limbs and PE involving a thrombus traveling to the lungs. LL DVTs are more likely to cause PE than UL DVT. DVT and PE can be asymptomatic or will cause symptoms based on the thrombus location. Furthermore, coexistent DVTs occur in 50%-60% of patients with symptomatic PE.

Typically, patients present with sudden-onset breathlessness, desaturation, and hypoxia on arterial blood gas analysis. Hypoxia in the presence of a normal chest X-ray suggests PE. Diagnosis can often be established by computed tomography pulmonary angiogram or ventilation-perfusion scan[32]. DVT can easily be diagnosed by Doppler scans of both the UL and LL. Recently, a prospective bedside study used electrical impedance tomography with saline contrast to diagnose PE but needs further validation[66]. This could be useful since it is hazardous to shift very unstable patients to a scanner. A PE severity index (PESI) score has been developed to stratify patients based on their clinical condition. The PESI allows calculation of the predicted 30-day mortality at presentation[67,68].

Often, the diagnosis of PE becomes elusive in a hypoxic patient in the ICU who is receiving ventilation. The cause could appear to be multifactorial including infection or rejection, and PE is not usually suspected clinically because of the institution of thromboprophylaxis. Burns and Iacono[69] reported a 19.5% incidence of clinically unsuspected PE. Unexplained causes of hypotension when usual causes are ruled out could be due to PE. A case report regarding a fatal unsuspected massive saddle PE that was diagnosed on the 11^th postoperative day by transesophageal echocardiogram points to the need for a high degree of suspicion for diagnosing PE[70]. Atypical presentations of pulmonary edema due to an increased flow in the unaffected branches of the pulmonary artery have been described[71].

Management of PE following LT: After confirmation of diagnosis, the primary therapy is pharmacological with the aim of appropriate anticoagulation if the patient is clinically stable with normal hemodynamics. Based on the clinical condition and urgency, pharmacological agents include intravenous infusion of unfractionated heparin or thrombolytic agents (which are contraindicated immediately after LT). Subcutaneous injections of low molecular weight heparin such as enoxaparin or oral drugs using vitamin K antagonists such as warfarin are the most common agents used. These drugs may be monitored by measuring anti-Xa levels (enoxaparin) and the international normalized ratio to assess the risk of bleeding[72,73].

Direct oral anticoagulants[74], also known as non-vitamin K antagonist oral anticoagulants[75], act directly by inhibiting either thrombin (factor IIa) or activated factor Xa. Drugs such as dabigatran inhibit fIIa, while drugs such as rivaroxoban[58], apixaban[76], and edoxaban inhibit fXa. A study by Mansell et al[77] advised caution for the concurrent use of apixaban along with tacrolimus because it caused higher levels of apixaban and bleeding. They recommended further studies prior to safe administration of apixaban.

In patients who are critically ill due to hypotension with acute right ventricular failure, the implementation of peripheral ECMO may be considered at the bedside. A systematic review reported good outcomes with ECMO in this scenario[78]. However, a study by Kaso et al[79] did not show a difference in survival in patients treated with or without ECMO. Other options in critical scenarios include percutaneous mechanical thrombectomy[80] or surgical embolectomy. Mengers et al[81] reported a rare instance of chronic thromboembolic pulmonary hypertension that developed after LT and was successfully treated by pulmonary thromboendarterectomy.

Association of PE and development of CLAD: A recently published study in 2024 reported a significantly higher risk of development of CLAD and death in patients who developed PE after LT[15]. However, risk stratification by the PESI score had no correlation to the development of CLAD. While the authors conceded that the development of CLAD may occur via unclear mechanisms, they suggested a lack of collateral blood flow or a heightened inflammatory response led to immune activation.

Association of PE and pulmonary infarction: The presence of the dual blood supply in normal lungs makes the likelihood of pulmonary infarction low after PE. In the general population, pulmonary infarction occurred in 10% of cases following PE[82]. In LT patients, the incidence of pulmonary infarction following PE was 37.5%[83]. Burns and Iacono[64], in their postmortem study of patients who died after LT, classified deaths as early (within 30 days), intermediate (30 to 365 days), or late (> 1 year). Among the pulmonary infarcts, these investigators found that 43.8% occurred among the early deaths, while 20.0% and 25.0% of pulmonary infarcts occurred in the intermediate and late deaths, respectively. This finding revealed that the incidence of pulmonary infarcts in the first 30 days after LT was still high despite the numerous interventions.

Persistence of a long-term prothrombotic state after LT: Sáez-Giménez et al[54] studied the levels of clotting factors at regular intervals after LT in a prospective study involving 48 patients. The authors noted that while most of the markers of a procoagulant state normalized and reached baseline by 2 weeks, the levels of factor VIII and von Willebrand factor remain elevated for up to 1 year after LT. This hypercoagulable state could explain the increased incidence of VTE months after LT.

Pharmacological thromboprophylaxis against VTE: Among the preventive measures against VTE, pharmacological means are the most widely accepted method. Scoring systems to evaluate the probability of PE clinically include the Wells score and the Geneva score. These scores can identify patients who will benefit from pharmacological prophylaxis. Padua and Caprini scores can be used to identify patients at high risk of developing VTE to institute preventive pharmacological measures. Models such as PESI/simplified PESI stratify patients with PE based on severity and treat appropriately. Patients awaiting LT are often limited in their exercise tolerance and have prolonged periods of immobility, thereby increasing the risks of VTE. Appropriate preventive measures must be undertaken, and patients should be reevaluated at regular intervals. The biggest challenge is patients who have a very high bleeding risk in whom use of anticoagulants is hazardous. In such cases, other means such as mechanical devices like sequential compression devices or compression stockings may be used.

CONCLUSION

A prothrombotic milieu exists for patients receiving LT and starts in the preoperative period, continues throughout the perioperative period, and extends into the postoperative period. There is a heightened risk of DVT and PE during all three periods of LT. Many patients remain asymptomatic, and screening protocols can successfully identify these asymptomatic patients. Apart from the well-known effects on bronchial ischemia and airway complications, it has now been shown that PE may play a part in the development of CLAD. Increasing regular screening, optimizing prophylaxis, and ensuring early mobilization and prompt removal of vascular catheters are preventive measures that could be undertaken. Striving to maintain the bronchial microenvironment should be prioritized. The bronchial microenvironment requires a dual blood supply, lymphatic channels and drainage, and nerve supply that exerts an effective control on the function of the bronchial microenvironment. While BAR may restore bronchial blood supply, the denervated state of the lung allograft and disconnected lymphatic system remains unchanged. In patients awaiting LT, avoiding prolonged periods of immobilization with nutritional, respiratory, and physical rehabilitation are important measures to prevent VTE after LT. Awareness of the possibility of VTE and regular clinical assessment and surveillance will improve future outcomes.