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Massive Fulminant Thrombosis During Liver Transplantation in a Patient With a Previously Unknown Antithrombin Pathway Mutation

Bezinover, Dmitri MD, PhD*; Sugino, Shigekazu MD, PhD; Imamura-Kawasawa, Yuka PhD; Bell, Matthew S. MD*; Kadry, Zakiyah MBChB§; Janicki, Piotr K. MD, PhD*

doi: 10.1213/XAA.0000000000000396
Case Reports: Case Report

We describe a case of fulminant intraoperative thrombosis during deceased donor liver transplantation. Despite significant medical bleeding, the patient suddenly developed diffuse thrombosis in all chambers of the heart and pulmonary vasculature resulting in intraoperative death. The patient’s postmortem genetic analysis demonstrated a deleterious missense mutation in a coagulation pathway gene, SERPINC1, which codes for antithrombin III. The level of antithrombin III was not available to directly prove the causality of thrombosis, but our findings suggest that this mutation, in combination with antifibrinolytic administration in a hypercoagulable cirrhotic patient, might have contributed to the development of this catastrophic thrombotic event.

From the *Department of Anesthesiology and Perioperative Medicine, Penn State College of Medicine/Penn State Hershey Medical Center, Hershey, Pennsylvania; Department of Anesthesiology and Perioperative Medicine, Tohoku University School of Medicine, Sendai, Japan; Department of Pharmacology, Penn State College of Medicine/Penn State Hershey Medical Center, Hershey, Pennsylvania; and §Department of Surgery, Penn State College of Medicine/Penn State Hershey Medical Center, Hershey, Pennsylvania.

Accepted for publication June 9, 2016.

Funding: None.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

D.B. and S.S. contributed equally to this work.

Address correspondence to Dmitri Bezinover, MD, PhD, Department of Anesthesiology, Penn State Hershey Medical Center, Penn State College of Medicine, 500 University Dr, P.O. Box 850, Hershey, PA 17033. Address e-mail to

End-stage liver disease (ESLD) is associated with significant hypercoagulability.1 This risk is even greater if the transplant recipient has a hereditary predisposition for thrombosis. Coagulation cascade manipulation in these patients can be associated with significant thrombotic events.2 We report a case of sudden, catastrophic thrombosis concomitant with severe medical bleeding, which was being managed with both blood products and tranexamic acid (TXA) administration. We hypothesized that a genetic error in a component of the coagulation system, in combination with the administration of antifibrinolytics in the face of an underlying hypercoagulable state, might have contributed to this event. Whole-exome sequencing was performed on blood and tissue specimens obtained at autopsy to identify potential deleterious genetic mutations in the coagulation pathway. The patient’s family reviewed the manuscript and gave written informed consent for publication. The consent was obtained from the family because the patient died during this case.

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Table 1.

Table 1.

Figure 1.

Figure 1.

A critically ill 51-year-old woman with ESLD (ie, Model for End-Stage Liver Disease score of 40) presented for orthotopic liver transplantation (OLT). Continuous renal-replacement therapy (CRRT) was started before transplantation because of acute onset renal failure, secondary to type I hepatorenal syndrome. On arrival in the operating room, spontaneous bleeding was noted from the patient’s nose, mouth, and several skin sites. Laboratory tests (Table 1) and thromboelastogram (Figure 1A) confirmed a severe coagulopathy. In addition to standard American Society of Anesthesiologists monitors, a transesophageal echocardiography probe was placed. During the preanhepatic phase, the patient received 2 U packed red blood cells, 6 U fresh frozen plasma, 10 U cryoprecipitate, and 2 U platelets. Because of the lack of both subjective and objective improvement in coagulation, an infusion of TXA (10 mg/kg/h) was begun after discussion with the surgical team. A repeat thromboelastogram demonstrated partial coagulation improvement (Figure 1B). During liver dissection (preanhepatic phase of OLT), the patient developed a sudden pulseless electrical activity cardiac arrest. This event occurred during dissection of the liver and approximately 40 minutes after starting the TXA infusion. Transesophageal echocardiography demonstrated massive, diffuse thrombosis in all chambers of the heart (Supplemental Digital Content 1, Video, The extracorporeal membrane oxygenation team was alerted, but the patient was deemed not to be a candidate for intervention. Despite intensive resuscitative efforts, the patient died 48 minutes after the onset of arrest. Autopsy revealed clots in all heart chambers, inferior vena cava, pulmonary artery, and portal vein, as well as diffuse pulmonary hemorrhage and fibrin deposits throughout the pulmonary vasculature.

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Considering the extent and severity of thrombosis that occurred, an inherited predisposition to hypercoagulability was considered. To determine possible unknown mutations in the coagulation pathway, circulating cell-free DNA was extracted from a cryopreserved recipient serum sample obtained preoperatively, which was followed by sequencing of the recipient exome (Supplemental Digital Content 2, Supplemental Methods, Selected coagulation pathway genes were analyzed for nonsynonymous (ie, protein coding) variants. Observed polymorphisms were verified with DNA from the patient’s liver samples with the use of selected gene fragment polymerase chain reaction amplification followed by direct Sanger sequencing. For further verification, reverse-transcription polymerase chain reaction was performed on RNA isolated from the formalin-fixed liver samples followed by direct Sanger sequencing.

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Figure 2.

Figure 2.

Table 2.

Table 2.

All nonsynonymous variants detected in coagulation pathway genes are presented in Table 2. One variant in SERPINC1 (Table 2, in bold) has not been reported previously. This single-nucleotide polymorphism causes a missense mutation (A to G base change [T to C on the complementary strand] in chromosome 1: 173873157) in exon 7 of the SERPINC1 gene. This results in an amino acid change of isoleucine to threonine in position 422 of antithrombin III (ATIII; NP_000479.1). The presence of this genome mutation was subsequently verified by both direct Sanger sequencing of the patient’s serum and post-mortem liver samples, and mRNA transcription of the SERC1A gene obtained from the patient’s liver sample (Figure 2). The potential for this mutation having functional consequences was demonstrated using DUET, a web-based computational program designed to study missense mutations in proteins (, predicting the destabilizing effects of new mutations on ATIII (Supplemental Digital Content 3, Supplemental Figure, No other potentially damaging variants were observed in any coagulation pathway gene (Table 2).

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Verification of expression of the SERPINC1 mutation in our patient indicates that she was a heterozygous carrier of a new type of deleterious mutation in this gene, which is responsible for ATIII protein coding. ATIII is a α2-globulin protease inhibitor synthesized in the liver and inhibits factors IIa and Xa. Hereditary ATIII deficiency has a prevalence of 1:500 to 1:50003 and results from an autosomal-dominant heterozygous mutation (homozygous variant is likely incompatible with life). Hereditary ATIII deficiency (caused by >220 known genetic variants) can be classified as type I or type II based on the specific SERPINC1 mutation. Individuals with type I mutations have only 1 working copy SERPINC1 in each cell, resulting in ATIII activity approximately half normal. Type I mutations account for only 12% of ATIII deficiency but are responsible for 60% of pathologic clotting events.3

Type II deficiency (88% ATIII mutations, but responsible for only 40% of clotting events) results in production of ATIII with reduced activity.3 Type II deficiency can be subdivided on the basis of whether there is altered binding to the target protease (type IIa), altered heparin binding (type IIb), or an altered interaction between ATIII and thrombin (type IIc). This distinction has important clinical significance and indicates that the type of ATIII defect modulates not only the risk of thromboembolism but also the location of the clot (arterial versus venous system).4 Lack of sufficient biological material from our patient prevented us from further characterizing the ATIII deficiency subtype.

Although no significant thrombotic events had been reported in our patient before transplantation, a catastrophic thrombosis occurred intraoperatively. For affected individuals, the incidence of thromboembolism usually increases with age and can be as high as 50% by 50 years of age.3 Considering the heterozygous character of this mutation, the clinical presentation of thrombotic events is likely to be related to additional factors, such as the administration of antifibrinolytics, the use of continuous CRRT, and/or hypercoagulability related to ESLD itself.

Severe thrombotic complications associated with antifibrinolytic administration in patients with ATIII pathway mutations have been described for other genetic errors in the coagulation pathway, and, as in our case, those patients had no history of thrombosis.5 Because 30% to 80% of carriers of ATIII mutations have thrombotic complications during their lifespan, any modulation of the coagulation system in such patients can be associated with significant thromboembolic risks.

Liver failure is associated with profound disruption in a patient’s coagulation profile that includes changes not only in the production of coagulation factors and platelets but also in endothelial function, which results in a new unstable balance.6 There is up to a 75% decrease in levels of liver-dependent coagulation (factors II, V, VII, IX, and X) and anticoagulation factors such as proteins C, S, ATIII, plasminogen, antiplasmin, and ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) (responsible for inactivation of von Willebrand factor) and up to a 200% increase in levels of liver-independent factors, including factor VIII, von Willebrand factor, and plasminogen activator inhibitor 1 in vascular endothelium.6,7 A significant reduction in endothelial production of tissue factor pathway inhibitor necessary for inactivation of factor Xa also has been demonstrated.6 These changes in factor levels could be responsible for shifting the coagulation equilibrium toward hypercoagulability.6,8,9 The use of antifibrinolytics in this unbalanced situation might precipitate thrombotic complications. Antifibrinolytics (lysine analogs), such as ε-aminocaproic acid and TXA, block lysine binding sites on plasminogen. This prevents binding between plasminogen activator–plasmin complexes and fibrin with subsequent inhibition of fibrinolysis.

Despite significant reductions in transfusion requirements, antifibrinolytic use, in fact, has been associated with severe thrombotic complications.2 Gologorsky et al10 reported severe thrombotic events after graft reperfusion in patients receiving TXA. Warnaar et al11 demonstrated that >50% of cases of pulmonary emboli and intracardiac clotting during OLT were associated with the administration of antifibrinolytics. The risks of antifibrinolytic-induced thrombosis during OLT can be exacerbated by pathologic conditions such as acute renal failure or hemodialysis and genetic factors including ATIII deficiency.

It also has been demonstrated that dialysis catheters used for CRRT can be associated with an increased risk of thrombosis, which is directly related to the duration the catheter was in place.12 CRRT in our patient was performed using a 9-Fr catheter placed in right femoral vein. This catheter was placed, and CRRT started, 3 days preoperatively and continued throughout surgery. Although this may have been an additional factor contributing to the thrombotic event in our patient, thromboses identified by Stavroulopoulos et al12 were associated with catheters that were in place for weeks, not days.

Although we were unable to measure the concentration and activity of ATIII preoperatively in our patient, and therefore do not have direct proof that this ATIII pathway mutation was the cause of the thrombotic event, considering the timing, extent, and fulminant character of thrombosis, it is very likely that this mutation, in combination with the other factors mentioned, contributed to this event.

It is important to recognize that hypercoagulability is an essential characteristic of ESLD. This understanding has already led to significant changes in patients’ preoperative evaluation in many transplant centers including routine screening for hypercoagulable syndromes. As genomic screening tests become more affordable and precise, screening for functional variants in the coagulation pathway should be considered.

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