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From the Department of Anesthesiology, University of Minneapolis, Minneapolis.
Address correspondence and reprint requests to Ioanna Apostolidou, MD, Department of Anesthesiology, University of Minneapolis, B515 Mayo, MMC 294, 420 Delaware St., S.E., Minneapolis, MN 55455. Address e-mail to apost015{at}umn.edu.
Abstract
We present a patient with end-stage heart failure and heparin-induced thrombocytopenia Type II, who required cardiopulmonary bypass (CPB) during a repeat implantation of a left ventricular assist device for long-term circulatory support. Bivalirudin was selected for anticoagulation during CPB, with concomitant infusion of aprotinin, in an effort to ameliorate blood loss. Nonetheless, profuse bleeding after CPB required massive transfusion of packed red blood cells, multiple coagulation factors, and platelets. Because of persistent bleeding, a single dose of recombinant factor VIIa (rFVIIa, 7.2 mg) was administered as rescue therapy. Within minutes, a large left atrial thrombus was detected by transesophageal echocardiography. We believe this is the first documentation of acute left atrial thrombus formation immediately after a single dose of recombinant factor VIIa administration during a left ventricular assist device implantation.
A left ventricular assist device (LVAD) is increasingly used as a bridge to cardiac transplantation and for destination therapy in patients with end-stage heart failure. LVAD therapy often presents complex hematologic challenges.1 Thromboembolism is a significant risk for patients during and after LVAD implantation because of concurrent activation of the coagulation and fibrinolytic systems. It occurs in up to 35% of patients with adverse sequelae.2–4 Coagulopathy during and immediately after LVAD implantation is commonly encountered because of multiple factor deficiencies. Thus, transfusion of blood products, and specific pharmacologic interventions to achieve hemostasis, is often required to establish cardiovascular stability in this vulnerable patient population. In addition, patients with preexisting heparin-induced thrombocytopenia (HIT) are at increased risk for perioperative prothrombotic events5,6 and adverse outcome after cardiac surgery.7,8 We present a patient with preexisting HIT and ventricular assist device, who required reimplantation of a HeartMate XVE LVAD device (Thoratec Corporation, USA). This presented simultaneous intraoperative anticoagulation and hemostatic challenges.
CASE REPORT
A 59-yr-old man in postmyocardial infarction cardiogenic shock and with a history of diabetes mellitus and hyperlipidemia was emergently transported from an outside hospital to our operating room (OR) for placement of a biventricular assist device, the Levitronix Extracorporeal Blood Pumping System (Levitronix, USA). The sequence of recent events was as follows: 12 days before our hospital admission, the patient had had a 4-vessel coronary artery bypass grafting surgery in another institution and he was discharged home. He was readmitted to the outside hospital with an acute myocardial infarction due to a new occlusion of the left main and circumflex coronary arteries and was then transferred to our institution because of cardiogenic shock. During interhospital transport, he suffered a 5-min cardiac arrest but was resuscitated promptly. On arrival in the OR, he was mechanically ventilated, and his cardiac function was supported by multiple inotropic drugs (epinephrine 0.01–0.05 µg · kg–1 · min–1, dopamine 15 µg · kg–1 · min–1) and intraaortic balloon pump. Urgent cardiopulmonary bypass (CPB) was instituted via reopening of the median sternotomy and after routine systemic heparinization. Transesophageal echocardiography (TEE) showed severe global hypokinesis with an estimated ejection fraction of 5% and enlarged left atrial (LA) and left ventricular chamber dimensions. No intracavitary thrombus was detected. Cannulation sites for the Levitronix LVAD included the LA via the right superior pulmonary vein (inflow) and the ascending aorta (outflow). Cannulation sites for the Levitronix right ventricular assist device included the right atrium (inflow) and the pulmonary artery (outflow). Postbypass coagulopathy was treated with the transfusion of multiple blood products (15 U of platelets, 6 U of fresh frozen plasma, 16 U of cryoprecipitate, and 8 U of packed red blood cells). Anticoagulation with heparin was resumed the next day, and his postoperative course was stabilized with improving renal and neurologic function. However, on postoperative day 11, a diagnosis of HIT Type II was based on a rapid decrease in the platelet count from 122,000 to 27,000 cell/mm3 within 24 h and positive antibodies against platelet factor-4 (PF4)/heparin complexes using enzyme-linked immunoassay (HIT screen = 0.64, ELISA, GTI-PF4). Anticoagulation was continued with lepirudin and the platelet count recovered progressively to 120,000 cells/mm3 during the next 24 h.
The patient returned to the OR for intracorporeal LVAD placement, HeartMate XVE, 13 days after admission. Lepirudin was stopped the morning of surgery. Preoperative laboratory values showed hemoglobin: 8.3 g/dL, platelet count 117,000 cells/mm3, partial thromboplastin time (PTT) 70 s, international normalized ratio (INR) 1.65, and creatinine 1.55 mg/dL. TEE performed before Levitronix explantation displayed no clot in the cardiac chambers (Fig. 1; Video 1, please see video clip available at www.anesthesia-analgesia.org). Aprotinin infusion was used at a half-dose regimen (1 million kallikrein inhibiting units (KIU) IV load over 20 min, 1 million KIU pump prime, and 250,000 KIU/h IV continuous infusion) and was continued until the end of the procedure. Based on the recommendation of a hematologist, anticoagulation for CPB was achieved with IV bolus of 50 mg (0.63 mg/kg) bivalirudin, followed by a continuous infusion of 2 mg · kg–1 · h–1. An additional dose of 50 mg of bivalirudin was added to the CPB priming solution. The dose was determined from the package insert recommendations for percutaneous coronary interventions and regimens used in earlier CPB procedures. Activated clotting time (ACT, Medtronic) was used to monitor anticoagulation (Fig. 2), since ecarin clotting time was not available to us. The ACT peak was 875 s at 90 min on CPB. The duration of CPB was 2 h, and the bivalirudin infusion was discontinued 7 min before CPB separation. Ten units of packed red blood cells were transfused during CPB to maintain hemoglobin concentration 8–10 g/dL, and ultrafiltration was used to remove 2400 mL of fluid. The biventricular assist device Levitronix system was explanted, and a HeartMate XVE LVAD was implanted with the inflow conduit attached to the apex of the heart and the outflow conduit attached to the ascending aorta. The patient required inotropic support with epinephrine (0.03 µg · kg–1 · min–1), milrinone (0.5 µg · kg–1 · min–1), and dopamine (3 µg · kg–1 · min–1) for separation from CPB as the LVAD flow was optimized. Severe postbypass bleeding was encountered, complicated by the inability to "reverse" the bivariludin and by dilutional and consumptive coagulopathy with a platelet count of 49,000 cells/mm3, PTT >240 s, INR >10, and fibrinogen level of 257 mg/dL (Table 1). The ACT was 605 s at 30 min off CPB and remained above control levels at 264 s 2.5 h post-CPB (Fig. 2). Despite continuing transfusion of blood products, which included 15 U packed red blood cells, 10 U of fresh frozen plasma, 6 donor packs of plasmapheresis platelets, and 12 U of cryoprecipitate, coagulopathy persisted 3 h after separation from CPB. Finally, after consultation with hematology and cardiac surgery, and 190 min after CPB, recombinant factor VIIa (rFVIIa) (90 µg/kg, total 7.2 mg) was administered IV over 5 minutes. Shortly after, TEE interrogation showed a new, large echodensity in the LA consistent with thrombus (Fig. 3; Video 2, please see video clip available at www.anesthesia-analgesia.org). The multilobular organized structure located at the level of the right upper pulmonary vein with extension to the left upper pulmonary vein was mobile and measured approximately 1 cm x 3 cm. Despite high-velocity, turbulent flow (detected by color Doppler flow, Fig. 4; Video 3, please see video clip available at www.anesthesia-analgesia.org) between the thrombus and the origin of the left upper pulmonary vein in the LA, the thrombus did not interfere with mitral valve leaflet motion and transmitral Doppler flow signal. Thrombotic strands were also noted in the inferior vena cava and hepatic veins. Comparative pre-CPB pictures were devoid of clot formation (Fig. 1; Video 1).
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After consideration of all management options, including reinitiation of CPB and LA thrombectomy, the decision was made to proceed with conservative treatment and postoperative anticoagulation with lepirudin. Coagulation values gradually improved with INR decreased to 2.4 and PTT to 115 s at the end of the procedure (Table 1). Total estimated blood loss was 10,000 mL and urine output 1435 mL. The total amount of blood products transfused was 30 U of packed red blood cells (20 U after CPB), 15 U of fresh frozen plasma, 8 donor packs of plasmapheresis platelets, 12 U of cryoprecipitate, and 2000 mL cell saver blood during the 7 h from the CPB separation to intensive care unit transfer.
The first week postoperative course was complicated by exploration for bleeding that was causing cardiac tamponade (post-LVAD day 1), and transient deterioration of the patient’s renal function (creatinine 2.4 mg/dL). He developed unstable supraventricular tachycardia resistant to pharmacologic and electrical treatment. An episode of generalized tonic clonic seizures ensued. The appearance of the LA thrombus was unchanged in serial postoperative TEE and transthoracic echocardiograms. Lepirudin was stopped because of upper gastrointestinal hemorrhage.
At 2 wk in the intensive care unit, the patient remained tracheally intubated and unable to follow commands despite discontinuation of sedatives, and he required tracheostomy. A computed tomography scan of the brain showed multiple small hypodense areas in the centrum semiovale. There was patchy loss of gray-white matter differentiation in right and left posterior hemisphere, as well as in the basal ganglia, interpreted as anoxic encephalopathy and possible small cardioembolic events.
Despite his initial grave prognosis, 1 mo later, the patient was awake and alert with improving upper and lower extremity strength and intact cranial nerves. He was placed on aspirin and was discharged to a cardiac rehabilitation center before home discharge. Subsequent computed tomography of the brain showed no acute intracranial pathology. Five months later HIT Type II antibodies were not detectable by ELISA (HIT screen negative). Seven months after the LVAD, he underwent heart transplantation and received systemic heparinization for CPB without complications.
DISCUSSION
Complex hemostatic abnormalities occur frequently after LVAD insertion.1–4 The case presented here was unique because of the combination of a repeat procedure in a patient with HIT requiring bivalirudin anticoagulation for CPB, and the diagnosis of acute LA thrombus formation after a single dose of rFVIIa. The postoperative course was complicated by multiple thromboembolic events and encephalopathy.
The presence of HIT presents tremendous management challenges for cardiac surgery patients.5–12 A number of strategies are available for anticoagulation during CPB, including the use of direct thrombin inhibitors. Since there are no neutralizing drugs for the direct thrombin inhibitors, their termination of action requires a combination of organ-dependent drug elimination and simultaneous clotting factor replacement. During this intense transfusion period, cardiovascular instability may result making rapid resolution of the coagulopathy a priority. In our case, this led to the decision to administer rFVIIa in conjunction with protein clotting factors and platelet transfusions. Unfortunately, an acute LA thrombus may have been the consequence.
The pathogenesis of LA thrombus formation involves complex interactions between platelets, circulating proteins, and the endothelium combined with dynamic forces of the circulation and blood stasis. Patients supported with a LVAD have evidence of increased thrombin generation and fibrinolysis, despite normal prothrombin time, PTT and platelet count.3 LA cannulation, postimplantation bleeding, and acute myocardial infarction before LVAD were found to be independent risk factors for LVAD-associated intracardial thrombus in a retrospective study of 51 patients receiving a LVAD.13 In our patient, a likely nidus for thrombus formation could have been the Levitronix LA cannula. Several other conditions that predispose to thrombosis were manifested in this patient. After multiple heparin exposures and while receiving heparin anticoagulation for the Levitronix assist devices, he developed HIT Type II, an immune-mediated condition characterized by acute decrease in platelet count from antibodies produced against complexes of PF4 and heparin.5,6 Patients with HIT are at risk for thrombotic complications from activation of platelets and increased thrombin generation.10 The incidence of HIT Type II in patients with ventricular assist devices has been reported to be 8%–10% and, when it is diagnosed after device implantation, is associated with a lower rate of procedural success.14 Our diagnosis of HIT Type II was based on the rapid decrease in the platelet count >50%, reaching a nadir of 27,000 cells/mm3 and the detection of HIT antibodies by immunoassay, following the College of American Pathologists criteria for HIT Type II diagnosis.15,16 Antigen assays (ELISA) have high sensitivity to detect PF-4/heparin antibodies, but lower specificity (74%–87%)15 than the activation assays (platelet aggregation assay or serotonin release assay). While antigen assays can misdiagnose HIT Type II, activation assays are technically demanding. Although there were no clinical signs of thrombosis during the time of platelet decrease and recovery, patients with HIT are at risk for thrombotic events even after the platelet count returns to normal.17 Sites of preexisting pathology, such as intravascular catheters and devices, may contribute to thrombosis, which has a mortality of 30%.18
In patients with HIT Type II, alternative anticoagulants include direct thrombin inhibitors, such as lepirudin, argatroban, and bivalirudin.9,11,12 Their use is limited by a lack of specific antidote, bleeding complications, and requirement for a specific monitoring of anticoagulation by ecarin clotting time. The use of lepirudin before surgery in a patient with mild renal dysfunction may contribute to bleeding. For the surgery, we decided to use bivalirudin for its rapid elimination by proteolytic mechanism. (Elimination half-life is reported to be 25 min in patients with normal renal function and 57 min in patients with severe renal impairment.) Hemodialysis and ultrafiltration eliminate 25%–69% of bivalirudin based on the pore size of the filter used.19 Ultrafiltration was used in our patient only during CPB, and residual bivalirudin likely contributed to recalcitrant post-CPB bleeding. This required a massive transfusion of blood products, antifibrinolytic therapy and, lastly, rFVIIa as a rescue therapy. This intense antifibrinolytic and factor therapy could plausibly have enlarged the nascent thrombus triggered by the LA cannula in the setting of HIT Type II predisposition to thrombosis.
Our patient had an estimated blood loss of 10,000 mL, which was twice his blood volume. Massive transfusion of blood products, defined as the replacement of at least one blood volume in 24 h, causes further coagulopathy from hemodilution, hypothermia, and acidosis.20 Aprotinin, a serine protease inhibitor with antifibrinolytic and platelet-preserving activities, has been used during implantation of ventricular assist devices and reoperations for bleeding after device insertion.21 Although there are anecdotal case reports of pulmonary thromboembolism and cannula thrombosis in assist device placement,22 other small case series reported no thromboembolic complications associated with the use of aprotinin during assist device placement21 or in patients with HIT type II. Two cases of fatal thrombosis, one with Factor V Leiden, were associated with aprotinin infusion during deep hypothermic circulatory arrest.23,24
Currently, rFVIIa is increasingly being used off-label outside of its licensed indication in patients with refractory surgical bleeding,25,26 which is the treatment of bleeding conditions in patients with hemophilia with inhibitors. A large dose of rFVIIa induces further thrombin generation on activated platelet surfaces.27 Our patient received 90 µg/kg rFVIIa, the recommended dose in hemophilia. The minimal effective dose has not been established yet and a range from 11.1 to 180 µg/kg has been used.28 Although PTT and INR are shortened after the use rFVIIa, different methods to monitor its action based on thrombin generation are currently being evaluated. Intractable bleeding during cardiothoracic surgery, liver transplantation, trauma surgery, retropubic prostatectomy, and intracranial hemorrhage has been successfully managed with rFVIIa.28–30 However, 90% of thomboembolic events (n = 168) with rFVIIa reported to the Food and Drug Administration were identified in off-label uses of rFVIIa.31 A definite cause–effect relationship could not be established in these cases because of concomitant confounding conditions. In one trial, treatment with rFVIIa in patients with intracerebral hemorrhage at doses of 160 µg/kg had a higher rate of thromboembolic events.30 Conversely, a review of 13 clinical trials of rFVIIa in patients with coagulopathy caused by anticoagulants, cirrhosis, or severe traumatic injury showed no difference in the incidence of thrombotic events between rFVIIa and placebo.32 A case report of heart transplantation in a patient with HIT type II described management of severe post-CPB bleeding with a combination of strategies, which included rFVIIa administration, postbypass hemodialysis to decrease the plasma concentration of bivalirudin, and transfusion of coagulation factors.33 The authors reported no thrombotic complications. Unfortunately, there is little information regarding rFVIIa safety and thromboembolic potential, especially in the patient with multifactorial coagulopathy, and HIT who receives multiple transfusions. Risk versus benefit should be considered when operating on HIT patients, especially those undergoing complex cardiac surgery. Further, the off-label use of rFVIIa in patients with uncontrolled bleeding should be carefully evaluated for risk versus benefit.
Footnotes
Accepted for publication October 3, 2007.
REFERENCES
This article has been cited by other articles:
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  K. A. Tanaka, N. S. Key, and J. H. Levy Blood Coagulation: Hemostasis and Thrombin Regulation Anesth. Analg., May 1, 2009; 108(5): 1433 - 1446. [Abstract] [Full Text] [PDF]
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