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A Misguided Contraindication: International Normalized Ratio in Acute Liver Failure Precluding Thrombolysis for Massive Pulmonary Embolism: A Case Report

Long, Micah T. MD*; Gallo, Paul D. MD*; Hammel, Laura L. MD*; Coursin, Douglas B. MD*,†

doi: 10.1213/XAA.0000000000000856
Case Reports
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Massive pulmonary embolism and its treatment with thrombolysis both carry grave risks. Optimal management hinges on determining the risk-to-benefit ratio of thrombolytic administration. For patients with liver dysfunction, assessing bleeding risk is challenging because they may have elevations in the international normalized ratio yet be hypercoagulable. We describe a patient with massive pulmonary embolism and new-onset liver failure, who—absent contraindications—warranted thrombolysis. Initial laboratory values, however, revealed an elevated international normalized ratio, which precluded lysis, despite a hypercoagulable Thromboelastogram. We believe that viscoelastic testing of coagulation is essential for evaluating coagulation in liver dysfunction, particularly when considering thrombolysis.

From the Departments of *Anesthesiology and

Anesthesiology and Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

Accepted for publication June 18, 2018.

Funding: None.

The authors declare no conflicts of interest.

Address correspondence to Micah T. Long, MD, Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, B6/319 UW CSC, 600 Highland Ave, Madison, WI 53792. Address e-mail to mtlong@wisc.edu.

Table 1.

Table 1.

Management of patients with pulmonary embolism (PE) hinges on the risk-to-benefit ratio of thrombolysis. Thrombolytic agents can improve survival, lower pulmonary artery pressures, improve oxygenation and perfusion, and possibly prevent the recurrence of PE.1 Nonetheless, lysis carries a risk of severe hemorrhage, including stroke, and a myriad of contraindications exist (Table 1).2 To aid decision making, risk stratification tools such as the Pulmonary Embolism Severity Index (PESI) score help to identify patients at higher risk of death, who may stand to benefit the most from lysis.3 In general, thrombolysis is avoided in low-risk patients who have neither shock, severe hypoxia, nor right ventricular dysfunction and—absent contraindications—deemed beneficial to high-risk, massive PE patients who present with hypotension, shock, or cardiac arrest.1,4 Intermediate-risk, submassive PE patients present with hemodynamic stability and without shock, but with right ventricular dysfunction. These patients may benefit from medical thrombolysis, particularly if there is evidence for right ventricular injury, but risks and benefits need to be evaluated meticulously and alternative dosing regimens considered.1,4–6

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CASE DESCRIPTION

Written consent was obtained from the patient to discuss the following case report.

A previously healthy 46-year-old man presented to the emergency department for progressive fatigue and mild shortness of breath, overlying 3 months of fatigue and worsened exercise tolerance. In the emergency department, he was afebrile, normotensive, and tachycardic to 181 beats/min. An electrocardiogram showed supraventricular tachycardia and adenosine administration revealed underlying atrial fibrillation. His laboratory values were most remarkable for transaminitis, hyperbilirubinemia, an increased international normalized ratio (INR), mild troponin and creatinine elevations, and a positive d-dimer (Table 2). Diltiazem and N-acetylcysteine infusions were initiated for management of atrial fibrillation and transaminitis, respectively, and a laboratory workup for acute liver failure begun.

Table 2.

Table 2.

Over the next hours, his shortness of breath worsened and repeat laboratory values showed worsening transaminitis, marked elevation of the INR, severe lactic acidosis, and elevated brain natriuretic peptide. A chest computed tomography-angiogram revealed diffuse extensive bilateral pulmonary emboli, right ventricular strain, and both right atrial and left ventricular thrombi. Heparin was initiated, and he was transferred to the intensive care unit for treatment of progressive hypoxia and increased work of breathing. He was emergently intubated, and mechanical ventilation was initiated using a lung-protective strategy with positive end-expiratory pressure of 7 and 70% fraction of inspired oxygen. Soon thereafter, he became hypotensive with blood pressures in the 80s/50s. Diltiazem was discontinued and a norepinephrine infusion begun. Bedside transesophageal echocardiogram revealed moderate right ventricular dilation with severe hypokinesis, a preserved apical wink, and an underfilled left ventricle, which was diffusely hypokinetic without regional wall motion abnormalities. Norepinephrine was transitioned to epinephrine at 0.04 µg/kg/min and inhaled nitric oxide initiated. He developed intermittent instability with ventilator dyssynchrony and hypoxemia, requiring sedation, opiates, and neuromuscular blockade to optimize his tenuous gas exchange. Vasoactive requirements escalated to include epinephrine, norepinephrine, and vasopressin, while amiodarone was infused to manage persistent atrial fibrillation. In addition, he developed acute kidney injury eventually requiring continuous hemodialysis.

With the development of shock and hypotension, the patient entered the massive, high-risk PE category with an estimated 30-day mortality by Pulmonary Embolism Severity Index score of 10%–24.5% (the highest risk category).3 Absent contraindications, his clinical picture warranted thrombolysis1,4; however, the rapid rise in his INR from 2.6 to 7.68 raised concern about the potential for subsequent life-threatening hemorrhage. Thus, to better assess his bleeding risk, a thromboelastogram (TEG; Haemonetics, Braintree, MA) was obtained. Results were consistent with a mild hypercoagulable state—contradicting the INR and consistent with his multifocal, severe thromboembolic disease (Figure 1). Nonetheless, in consultation with the hospital’s “Pulmonary Embolism Response Team,” thrombolysis was avoided due to INR elevation—the sole factor precluding thrombolysis.

Figure 1.

Figure 1.

Fortunately, with aggressive right ventricular support and ongoing therapeutic anticoagulation with heparin, the patient survived and was discharged from the hospital after 34 days of care. His liver failure resolved within 1 week, supporting the diagnosis of severe congestive hepatopathy. He was extubated 12 days after admission, and he remained on dialysis for approximately 6 weeks. His discharge echocardiogram showed an ongoing severe decrease in left ventricular function, severe right ventricular enlargement, and moderately elevated pulmonary pressures. The persistence of depressed left ventricular function suggested an underlying cardiomyopathy, which likely explained his previous months of fatigue and increased his risk of thromboembolic events. At the time of publication, he continues to be followed for atrial fibrillation and heart failure.

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DISCUSSION

Viscoelastic Testing of Coagulation

Evaluation for bleeding diathesis centers on history, physical, and laboratory evaluation. The prothrombin time assay, standardized to the INR, evaluates the vitamin K–dependent coagulation factors and protein C and S, providing insight into the extrinsic and common pathways of coagulation. The INR does not assess the independent intrinsic pathway, thrombin generation, clot strength, or the interactions among factors, the cell, and the vasculature. Thus, INR does not universally predict coagulation status.7

Coagulopathy in liver failure highlights limitations of the INR due to deficiencies in both procoagulant factors and native anticoagulants. Venous thromboembolism can occur in cirrhotic patients with elevated INRs, even with levels >2.2, dispelling the myth of “auto-anticoagulation” in liver failure.8 Fortunately, tests such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM; TEM International, Munich, Germany) can aid in the delineation of coagulation status in liver failure patients.9 These viscoelastic tests measure the developing clot by rotating a fixed pin with a clotting activator in a cup containing whole blood, then measuring the torque between the pin and the cup as the clot develops. This method thus incorporates factors, plasma, and cellular components of coagulation. The graphical output of the torque over time rapidly depicts the overlapping phases of coagulation—initiation, amplification, and propagation, and can be followed over an extended period to identify clot strength and even fibrinolysis (Figure 2).9,10 Insights into active elements reflected in each phase guides interpretation and management. For example, a prolonged R-time, suggesting delayed initiation, typically reflects decreased circulating procoagulant factors (eg, hemophilia), whereas hypercoagulable patients have short R- and K-times and steep α-angles (Figure 3).9,10 Importantly, viscoelastic tests can be modified by adding heparinase, platelet inhibitors, or even antifibrinolytic drugs to further delineate specific deficiencies in coagulation.9

Figure 2.

Figure 2.

Figure 3.

Figure 3.

TEG and ROTEM use has resulted in fewer transfusions in trauma patients and in those undergoing cardiac and hepatic procedures, including liver transplantation, without worsened hemorrhage and with possibly lower morbidity.9–11 Viscoelastic tests, however, are not perfect. Neither the TEG nor ROTEM have complete reference ranges in varied populations (eg, pregnancy), nor are they directly comparable.9 Further, they can fail to identify platelet dysfunction because the maximal clot strength relies heavily both on platelets and fibrinogen levels.9

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INR: A Misguided Contraindication

Our patient had massive PE and arrived in decompensating shock. Absent contraindications, thrombolysis is indicated in this situation.1,4 While traditional dosing for massive PE is alteplase 100 mg for an adult, optimal dosing has come into question. For example, Sharifi et al6 have trialed “safe” dosing of alteplase 50 mg for intermediate-risk submassive PE with good overall outcomes and no hemorrhagic complications, although their sample size was very small. Most conservatively, for patients with identified PE in the operating room undergoing liver transplantation—a group with clear contraindication to higher dose therapy—Mandell et al12 recommend 0.5–4 mg dosing, which at their center has yielded immediate hemodynamic improvement and clot lysis. For our patient, a dose of 100 mg would certainly be standard and routine for massive, high-risk PE, while a conservative dose of 50 mg may have been considered after stable vital signs on moderate-dose vasoactives for several hours.

Our patient’s INR, however, was thought to reflect excessive risk for hemorrhage and precluded thrombolysis. Because his TEG showed a mildly hypercoagulable state, we believe that the isolated interpretation of his INR was incorrect. Unfortunately, viscoelastic testing has not been evaluated as an adjunctive screening tool to assess hemorrhage risk after thrombolytic administration in PE. Two studies, however, have suggested that viscoelastic testing might help identify risk of hemorrhagic transformation after alteplase administration in acute ischemic stroke.13,14 Further, viscoelastic testing has quickly identified iatrogenic hyperfibrinolysis after thrombolysis in acute ischemic stroke, which can be managed with antifibrinolytic agents to mitigate hemorrhage.15

Due to the INR’s lack of accuracy in liver failure, viscoelastic testing of coagulation should be routine for all patients presenting with PE and liver dysfunction to accurately identify contraindications to lysis. Thrombolysis would likely have decreased our patient’s degree of right heart strain and systemic hypoperfusion, limited the severity of his acute kidney injury, shortened his duration of mechanical ventilation and intensive care unit stay, and decreased his risk of death. Further, thrombolysis may have decreased the risk of recurrence of PE.1 While we are immensely thankful that our patient survived with little long-term morbidity, we feel that his well-being is related to good fortune and effective supportive care. We are reminded that while it is better to be lucky than good, it is better to be lucky AND good and feel that lysis was indicated and would have given him the best absolute chance for meaningful survival.

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DISCLOSURES

Name: Micah T. Long, MD.

Contribution: This author helped prepare the manuscript.

Name: Paul D. Gallo, MD.

Contribution: This author helped prepare the manuscript.

Name: Laura L. Hammel, MD.

Contribution: This author helped prepare the manuscript.

Name: Douglas B. Coursin, MD.

Contribution: This author helped prepare the manuscript.

This manuscript was handled by: BobbieJean Sweitzer, MD, FACP.

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