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Anesth Analg 2005;101:1608-1612
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000184256.28981.2B

CARDIOVASCULAR ANESTHESIA

Four Cases of Cardiopulmonary Thromboembolism During Liver Transplantation Without the Use of Antifibrinolytic Drugs

Adam B. Lerner, MD, Eswar Sundar, MD, Feroze Mahmood, MD, Todd Sarge, MD, Douglas W. Hanto, MD, PhD, and Peter J. Panzica, MD

Departments of Anesthesiology and Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts

Address correspondence and reprint requests to Adam B. Lerner, MD, BIDMC Department of Anesthesia, West Campus, CC 540, 1 Deaconess Rd., Boston, MA 02215. Address e-mail to alerner{at}bidmc.harvard.edu.


   Abstract
Top
 Abstract
Introduction
 Case Report
 Discussion
 References
 
Orthotopic liver transplantation (OLT) is one of the most demanding surgical procedures performed. Intraoperative bleeding can be substantial and related to both surgical and nonsurgical causes. A less common but previously reported phenomenon is intraoperative cardiopulmonary thromboembolism precipitating major patient morbidity and mortality. In this paper, we present four cases of intraoperative thromboembolism during OLT. These cases were performed without the concomitant use of antifibrinolytic drugs. We performed a review and analysis of previously reported cases of intraoperative thromboembolism during OLT. Possible causes of thromboembolism, clinical management, use of thromboelastography, and the role of antifibrinolytic drugs are discussed.


   Introduction
Top
 Abstract
 Introduction
Case Report
 Discussion
 References
 
Orthotopic liver transplantation (OLT) is one of the most demanding surgical procedures. Intraoperative bleeding can be substantial and related to both surgical and nonsurgical causes. A less common but previously reported phenomenon is intraoperative pulmonary thromboembolism, which may be a cause of major patient morbidity and mortality. In this paper, we report on four such cases that occurred without the concomitant use of an antifibrinolytic drug. These four cases are summarized in Table 1, and one case (Patient 1) is presented in more detail. All of these cases were performed using the "piggy-back" anastomotic technique without the need for inferior vena cava (IVC) clamping or venovenous bypass.


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  		Table 1. Characteristics of Presented Cases

 


   Case Report
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 Abstract
 Introduction
 Case Report
Discussion
 References
 
The patient was a 62-yr-old man with a history of hepatitis C and alcoholic cirrhosis. He had a previous episode of deep vein thrombosis associated with a pulmonary embolus 1 yr before the current admission for transplant. He also had a history of several episodes of upper gastrointestinal bleeding. Preoperative laboratory examination revealed a prothrombin time (PT) of 14.1 s, International Normalized Ratio (INR) of 1.4, partial thromboplastin time (PTT) of 26 s, and a platelet count of 140,000/µL. Near the end of the preanhepatic phase, an episode of acute blood loss was encountered. The patient was treated with 600 mL of a one-to-one mixture of packed red blood cells and fresh frozen plasma. Laboratory findings sent at that time revealed a PT of 16.3 s, INR of 1.8, PTT of 33.3 s, platelet count of 111,000/µL, and a plasma fibrinogen level of 166 mg/dL. Thirty minutes later, with continued dissection of the liver, the patient became hypotensive with a systemic blood pressure of 70/45 mm Hg with simultaneous decreases in pulmonary arterial blood pressure and mixed venous saturation (Svo2). The hypotension was treated with the rapid infusion of blood products and bolus doses of phenylephrine. The surgical team successfully removed the patient’s liver during this time and was able to achieve improved hemostasis. However, the patient’s hemodynamic status did not improve despite the resuscitative efforts. His systemic blood pressure remained low, but increasing pulmonary artery pressures, up to 72/40 mm Hg, were noted. The Svo2 continued to decrease to 40%. Within moments, the patient’s oxygen saturation decreased to 70%, and he became bradycardic, with a heart rate of 40 bpm. Resuscitation with epinephrine and atropine was started without improvement. A transesophageal echocardiogram probe was inserted during this time and demonstrated a severely enlarged and depressed right ventricle with a mild global hypokinesis of the left ventricle. There was a large mobile echodensity consistent with thrombus present within the right atrium extending across the tricuspid valve into the right ventricle (Fig. 1). Portions of the mass were seen to dislodge and travel through the right ventricle into the pulmonary artery. Heparin 5000 U was administered IV and the resuscitation continued. Within 10 min, the patient’s hemodynamic profile began to improve. Transesophageal echocardiogram examination at that time revealed improved right ventricular function with only mild global right ventricular hypokinesis and disappearance of the thrombus seen earlier in the right atrium. Systemic blood pressures and Svo2 improved as pulmonary arterial pressures decreased. The surgical procedure then proceeded and finished uneventfully, with the patient making a full recovery.



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  		Figure 1. Transesophageal echocardiogram showing large thrombus in the right atrium (RA) extending through the tricuspid valve into the right ventricle (RV). LA = left atrium.

 


   Discussion
Top
 Abstract
 Introduction
 Case Report
 Discussion
References
 
Cardiopulmonary thromboembolism has consistently been reported as a rare event during OLT ((1–5). By our count, there are 12 articles within the medical literature that report on at least 23 cases of such events 1–12). Because we do not how many cases have remained unrecognized or simply unreported, it is impossible to know with certainty the true incidence of these complications. Gologorsky et al. (9) reported seven cases of intracardiac thrombosis in 577 liver transplants (1.2%) performed over 2.5 years. In this article, we report on 4 cases that have occurred within a two-year period at our institution, during which time 64 transplants were performed. This represents a significantly more frequent incidence (6.25%).

Treatment and outcome of patients who develop this complication depend to a large degree on the size and location of the thromboembolus. Resuscitative efforts should begin immediately and include combinations of inotropic, vasopressor, and fluid therapy. For unknown reasons, as reported by others and as occurred in our presented case, a significant number of patients seem to have resolution of their thromboemboli and secondary clinical signs within approximately 30 minutes of their onset (3,9). Several authors have reported the use of heparin (11) or thrombolytic drugs to help with clot dissolution (2,4,8,9), although complications from bleeding may be problematic. Others have reported cardiopulmonary thrombectomy, both with and without the use of cardiopulmonary bypass, in cases where resuscitative efforts were unsuccessful or prolonged (4,8,10). The results of these interventions have also been mixed.

In Table 2, we have summarized our review of the literature as it pertains to case reports of cardiopulmonary thromboembolism during OLT. A review of these data, which includes our 4 patients, reveals that the thromboembolic events occurred with a slight predominance during the reperfusion phase of the procedure, i.e., 37% of cases; 30% of cases occurred during preanhepatic and 33% during the anhepatic phase. In 11 of the 20 (55%) cases where its use or non-use was reported, venovenous bypass was not used. Antifibrinolytics were used in 69% of the 26 cases where use or non-use was reported. The intraoperative mortality rate was 30%.


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  		Table 2. Review of Literature

 

A multitude of factors may have played a role in the development of thromboembolic events in our cases and those previously reported. With the institution of the modified Model for End-Stage Liver Disease (MELD) score as the determinant for donor liver allocation in February 2002, more severely compromised patients are presenting for OLT (13,14). Many of these patients have had prolonged immobilizations because of physical limitations, as well as multiple hemorrhages or transfusions. Although most clinicians would consider these patients at low risk, given the predominance of hypocoagulability, these factors can increase the risk for blood stasis and perhaps make some susceptible to the formation of thrombi in deep veins. Comorbidities in these patients may also increase the risk for thrombosis. Patient 1 in our series, for example, had a history of deep vein thrombosis and pulmonary embolus, and Patient 4 had a history of lymphoma. It is possible that preexisting thrombi could have become detached or dislodged during the surgical procedure and resulted in cardiopulmonary embolism.

Changes in surgical technique, especially the increased use of IVC-sparing techniques (piggy-back technique) (15), which decrease the need for venovenous bypass, could also have an impact on the incidence of thromboembolism. However, even during the piggy-back procedure, when the confluence of the hepatic veins is clamped, there can still be some compromise of vena caval flow leading to distension of the IVC below the clamp. This is a potential site of venous stasis that could predispose to the formation of clot in the IVC that could later embolize after removal of the clamp. Suriani et al.1 suggest that venovenous bypass could have a protective effect on intraoperative thromboembolism by decreasing intraoperative venous stasis in both the portal and systemic systems.

Consideration must also be given to the transfusion practices used in each case. At our institution, before the onset of the cases presented herein, in addition to clinical assessment of coagulation, the basic goals of keeping INR less than 2, fibrinogen more than 150 mg/dL, and platelet count more than 100,000/µL were used. These goals were achieved through the transfusion of combinations of fresh frozen plasma, cryoprecipitate, and platelets. Although each center will have different thresholds, it is unclear whether it is possible to cause cardiopulmonary thromboembolism by transfusing to these or, in fact, any other goals.

As was true in all four of our cases, most OLT patients demonstrate significant derangements in clotting function as characterized by PT, PTT, and platelet number. It is also clear that derangements of anticoagulation systems can occur at the same time. These derangements can result from several causes. They include decreased hepatic production of anticoagulants, such as protein C, protein S, and antithrombin III, and deficient clearance of procoagulants (16,17). Although several investigators have suggested that disseminated intravascular coagulation (DIC) may be a rare occurrence during OLT (18–20), coexisting disease processes may serve as a stimulus for DIC. DIC may then lead to thromboembolic events.

Although they are not used at our institution, much of the current literature on thromboembolism during OLT revolves around the use of antifibrinolytics (12,21,22). In 18 of the 27 (67%) cases now reported, an antifibrinolytic drug was used. Experience with antifibrinolytics during OLT has been reported from several centers (22–30). The rationale for their use is to prevent or decrease the fibrinolysis seen in approximately 40% of patients on reperfusion of the transplanted liver (31). Several studies have demonstrated the effectiveness of these drugs in preventing fibrinolysis and in reducing transfusion (23,29,32,33). Although the primary focus of these studies was intraoperative blood loss and transfusion requirements, none of the investigators found an increase in the occurrence of intraoperative or postoperative thromboembolic events in patients who received antifibrinolytic drugs.

Although antifibrinolytics were used in most cases, it seems that the role of these drugs in thromboembolism during OLT is yet to be definitively established.

Hypercoagulability, as defined by thromboelastography (TEG®) criteria (short R time, a large maximum amplitude, or a steep {alpha} angle), may be extremely common in OLT patients despite abnormal PT, PTT, and platelet number. In an abstract from De Wolf et al. (34), retrospective analysis revealed that 50% of 58 sequential patients undergoing transplant had hypercoagulable TEG® variables. Ben-Ari et al. (35) found that hypercoagulable TEG® variables were more common in patients with biliary cirrhosis (28% of patients with primary biliary cirrhosis, 43% of patients with primary sclerosing cholangitis, and only 5% of patients with noncholestatic cirrhosis). Of note, only 27% of patients with a hypercoagulable TEG® had lower than normal levels of protein C, S, or antithrombin III.

Of the 27 cases reported in the literature, TEG® was used in 13. In 9 of these 13 patients (69%), either the TEG® was consistent with hypercoagulability or the sample clotted premature to the analysis (taken to be a sign of hypercoagulability). In only three of these nine patients were the results of standard coagulation tests also reported. Of these patients, two had abnormal increases of PT and PTT, whereas one had normal results.

It is important to note that TEG® variables suggestive of hypercoagulability have been noted in other patient populations. Studies involving postpartum patients, morbidly obese patients, patients undergoing intracranial neurovascular procedures, and even in healthy adult liver donors have found TEG® variables consistent with hypercoagulability (36–39). Although a recent cohort study did find a significant link between increased maximum amplitude and postoperative thrombotic complications (40), the clinical significance of hypercoagulable TEG® variables remains to be definitively determined.

Thromboembolism during OLT is a complex, multifactorial event with potentially devastating impact. Our four cases clearly emphasize this point. The small number of patients that both we and others have presented do not yet allow for definitive comment about all precipitating factors, prevention, and even treatment.

In conclusion, we have presented four patients with clinically significant and documented intraoperative thromboembolism during OLT without the concomitant use of antifibrinolytic drugs. We have discussed the uncertainties surrounding the true incidence of this complication and possible causes. We have discussed the uncertainty about the role of antifibrinolytics. We also consider the potential use of TEG® in identifying hypercoagulable states in OLT patients even when routine coagulation studies suggest hypocoagulability.


   Footnotes
 
1 1. Suriani RJ, Cutrone A, Cohen E, et al. Pulmonary thromboembolism during liver transplantation: is veno venous bypass protective? Liver Transpl Surg 1995;1:416A. Back

Accepted for publication July 5, 2005.


   References
Top
 Abstract
 Introduction
 Case Report
 Discussion
 References
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2005 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press