CASE REPORTS Catheter-directed thrombolysis
C A S E R E P O R T S
Use of argatroban and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis Brian Dee, Lindsey Lombardi Thomas, and Alison Gulbis
H
eparin-induced thrombocytopenia (HIT) is an antibodymediated adverse reaction to heparin products associated with a transient hypercoagulable state that increases the risk of arterial and venous thromboembolism (VTE). 1-4 HIT can occur in the absence of thrombosis (termed isolated HIT). When HIT is associated with thrombosis (termed HITT), it can lead to debilitating and lifethreatening complications, including stroke, myocardial infarction, deep vein thrombosis (DVT), pulmonary embolism (PE), and superior vena cava (SVC) syndrome. SVC syndrome is a medical emergency resulting from the physiological effects of obstruction of the SVC.5,6 While SVC syndrome is classically associated with malignancy, obstruction due to implantable i.v. devices is also a common etiology.5 Although SVC syndrome is associated with a myriad of signs and symptoms, facial swelling, dyspnea, cough,
Purpose. The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with argatroban plus catheterdirected thrombolysis (CDT) with alteplase is presented. Summary. A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upperextremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of argatroban was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the
upper-extremity edema, and chest pain are common.5 The cornerstones of SVC syndrome treatment include supportive care, management of
B rian D ee , P harm .D., BCPS, BCNSP, is Clinical Pharmacy Specialist—Critical Care/Nutrition Support; Lindsey Lombardi Thomas, Pharm.D., BCOP, is Clinical Pharmacy Specialist—Stem Cell Transplantation; and Alison Gulbis, Pharm.D., BCOP, is Clinical Pharmacy Specialist—Stem Cell Transplantation, Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston.
procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on argatroban. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on argatroban; ultimately, he was transitioned to warfarin for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. Conclusion. A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with argatroban and CDT with alteplase. Am J Health-Syst Pharm. 2014; 71:711-6
complications, and correction of the underlying cause.5,6 Treatment of HITT requires the discontinuation of all heparin prod-
Address correspondence to Dr. Dee ([email protected]). The authors have declared no potential conflicts of interest. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/0501-0711$06.00. DOI 10.2146/ajhp130132
Am J Health-Syst Pharm—Vol 71 May 1, 2014
711
CASE REPORTS Catheter-directed thrombolysis
ucts and the initiation of a nonheparin anticoagulant. In patients with HITT, the American College of Chest Physicians recommends the initiation of an i.v. direct thrombin inhibitor, in particular argatroban or lepirudin, over further use of heparin products or the initiation of a vitamin K antagonist, such as warfarin.7 Additionally, the direct thrombin inhibitor bivalirudin and the factor Xa inhibitor fondaparinux have been used for the treatment of HITT.7-11 Due to the absence of head-to-head trials of these medications, agent selection is generally based on patientspecific factors, pharmacokinetic properties, availability, and clinician experience. In cases of limb-threatening is chemia in HITT, which can be seen with extensive DVT or SVC syndrome, systemic anticoagulation with a nonheparin anticoagulant may be inadequate. Under these circumstances, mechanical removal of the thrombus or direct instillation of a thrombolytic into the thrombus may be necessary. Percutaneous mechanical thrombectomy and catheter-directed thrombolysis (CDT) have been used individually and in combination for acute limb ischemia caused by VTE.12-14 Thrombolytic agent selection, dosage, delivery technique, and duration of therapy in CDT vary widely in clinical practice. For patients receiving CDT for acute limb ischemia, the Advisory Panel on Catheter-Directed Thrombolytic Therapy of the Society for Cardiovascular and Interventional Radiology recommends alteplase dosing of 0.12–2 mg/hr and concomitant administration of subtherapeutic heparin (targeting an activated partial thromboplastin time [aPTT] 1.25–1.5 times the baseline value).15 However, the concomitant use of heparin with alteplase is problematic in the patient with HITT and acute limb ischemia, as heparin is absolutely contraindicated in this scenario. The clinical literature de712
scribing the use and management of alternative, nonheparin anticoagulants with alteplase during CDT is still very limited.16-18 Here we report the case of an oncology patient with HITT in whom argatroban and CDT with alteplase were used. Case report A 63-year-old Caucasian man (weight, 103.1 kg; height, 184 cm) with a history of amyloid light-chain amyloidosis with renal involvement was undergoing peripheral blood stem cell (PBSC) collection for an autologous stem cell transplant. He was admitted to the emergency department (ED) with syncope and swelling of the face and neck. Of note, the patient had received a right subclavian apheresis catheter 15 days prior to the ED admission in preparation for PBSC collection. Highdose granulocyte colony–stimulating factor (GCSF) therapy had been initiated 12 days prior to admission, and the patient had undergone four daily apheresis sessions starting 9 days prior to admission. Three days prior to ED admission, he was diagnosed with a right upper-extremity DVT at our institution and started on therapeutic anticoagulation with enoxaparin. The patient had been exposed to heparin flushes in the 15 days since placement of the apheresis catheter, and his platelet count had decreased from 222,000 cells/mL to 41,000 cells/mL during that time. Although HIT was included in the differential diagnosis, the patient’s thrombocytopenia was attributed to his apheresis treatments. Other pertinent information in the medical history included hypertension, dyslipidemia, and nephrotic syndrome with light-chain proteinuria. His outpatient medications included enoxaparin 100 mg subcutaneously every 12 hours, aspirin 81 mg daily, furosemide 40 mg twice daily, potassium chloride 20 meq daily, prava statin 40 mg daily, and olmesartan
Am J Health-Syst Pharm—Vol 71 May 1, 2014
20 mg daily. Pertinent laboratory values prior to admission and during hospitalization are presented in Table 1. The patient was admitted to the general medical floor with presumed SVC syndrome. Imaging revealed a new left upper-extremity DVT in the proximal midinternal jugular and subclavian veins, an extensive right upper-extremity DVT extending throughout the venous system to the SVC, and segmental PE in the right lung. Due to concern about potential HIT, an enzyme-linked immunosorbent assay (ELISA) for the HIT antibody and a serotoninrelease assay (SRA) were performed, and the patient was empirically initiated on a continuous i.v. infusion of argatroban (GlaxoSmithKline, Research Triangle Park, NC). The result of the ELISA for HIT antibody was reported as positive (optical density, 3.169; cutoff value, >0.4), as was the result of the SRA. On hospital day 6, the patient experienced brief episodes of loss of consciousness and stiffening during coughing spells. He was transferred to the medical intensive care unit (MICU) on hospital day 7 for the treatment of hypoxic respiratory insufficiency and acute renal failure requiring continuous slow lowefficiency hemodialysis (SLED) and for close hemodynamic monitoring. On hospital day 8, he underwent CDT and percutaneous mechanical thrombectomy, during which he was intubated for airway protection. Alteplase (Activase, Genentech, Inc., South San Francisco, CA) 0.2-mg/mL injection for infusion was prepared by reconstituting 50 mg of the drug in 0.9% sodium chloride injection for a total volume of 250 mL, and equal amounts were instilled into each arm, with a dwell time of approximately 10 minutes. Following CDT, a mechanical thrombectomy was performed and resulted in partial recanalization of the SVC and central veins; thrombosis of bilateral
Am J Health-Syst Pharm—Vol 71 May 1, 2014
a INR = International Normalized Ratio, aPTT = activated partial thromboplastin time, ALT = alanine transaminase, AST = aspartate transaminase, SLED = slow low-efficiency hemodialysis, IHD = intermittent hemodialysis, DVT = deep vein thrombosis, SVC = superior vena cava, MICU = medical intensive care unit, PMT = percutaneous mechanical thrombectomy, CDT = catheter-directed thrombolysis. b First heparin exposure occurred on day –15. c Prior to admission. d Patient receiving argatroban. e Not measured.
IHD Discharged home IHD Transferred to general medical floor IHD Continuous CDT stopped SLED Transferred to MICU None Presented with SVC syndrome None DVT diagnosed
SLED First PMT and CDT
SLED Second PMT, continuous CDT started
8.09 5.81 2.81 1.92 1.55 1.03 1.08
1.75
0.3 0.8 1
C A S E R E P O R T S
Use of argatroban and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis Brian Dee, Lindsey Lombardi Thomas, and Alison Gulbis
H
eparin-induced thrombocytopenia (HIT) is an antibodymediated adverse reaction to heparin products associated with a transient hypercoagulable state that increases the risk of arterial and venous thromboembolism (VTE). 1-4 HIT can occur in the absence of thrombosis (termed isolated HIT). When HIT is associated with thrombosis (termed HITT), it can lead to debilitating and lifethreatening complications, including stroke, myocardial infarction, deep vein thrombosis (DVT), pulmonary embolism (PE), and superior vena cava (SVC) syndrome. SVC syndrome is a medical emergency resulting from the physiological effects of obstruction of the SVC.5,6 While SVC syndrome is classically associated with malignancy, obstruction due to implantable i.v. devices is also a common etiology.5 Although SVC syndrome is associated with a myriad of signs and symptoms, facial swelling, dyspnea, cough,
Purpose. The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with argatroban plus catheterdirected thrombolysis (CDT) with alteplase is presented. Summary. A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upperextremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of argatroban was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the
upper-extremity edema, and chest pain are common.5 The cornerstones of SVC syndrome treatment include supportive care, management of
B rian D ee , P harm .D., BCPS, BCNSP, is Clinical Pharmacy Specialist—Critical Care/Nutrition Support; Lindsey Lombardi Thomas, Pharm.D., BCOP, is Clinical Pharmacy Specialist—Stem Cell Transplantation; and Alison Gulbis, Pharm.D., BCOP, is Clinical Pharmacy Specialist—Stem Cell Transplantation, Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston.
procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on argatroban. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on argatroban; ultimately, he was transitioned to warfarin for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. Conclusion. A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with argatroban and CDT with alteplase. Am J Health-Syst Pharm. 2014; 71:711-6
complications, and correction of the underlying cause.5,6 Treatment of HITT requires the discontinuation of all heparin prod-
Address correspondence to Dr. Dee ([email protected]). The authors have declared no potential conflicts of interest. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/0501-0711$06.00. DOI 10.2146/ajhp130132
Am J Health-Syst Pharm—Vol 71 May 1, 2014
711
CASE REPORTS Catheter-directed thrombolysis
ucts and the initiation of a nonheparin anticoagulant. In patients with HITT, the American College of Chest Physicians recommends the initiation of an i.v. direct thrombin inhibitor, in particular argatroban or lepirudin, over further use of heparin products or the initiation of a vitamin K antagonist, such as warfarin.7 Additionally, the direct thrombin inhibitor bivalirudin and the factor Xa inhibitor fondaparinux have been used for the treatment of HITT.7-11 Due to the absence of head-to-head trials of these medications, agent selection is generally based on patientspecific factors, pharmacokinetic properties, availability, and clinician experience. In cases of limb-threatening is chemia in HITT, which can be seen with extensive DVT or SVC syndrome, systemic anticoagulation with a nonheparin anticoagulant may be inadequate. Under these circumstances, mechanical removal of the thrombus or direct instillation of a thrombolytic into the thrombus may be necessary. Percutaneous mechanical thrombectomy and catheter-directed thrombolysis (CDT) have been used individually and in combination for acute limb ischemia caused by VTE.12-14 Thrombolytic agent selection, dosage, delivery technique, and duration of therapy in CDT vary widely in clinical practice. For patients receiving CDT for acute limb ischemia, the Advisory Panel on Catheter-Directed Thrombolytic Therapy of the Society for Cardiovascular and Interventional Radiology recommends alteplase dosing of 0.12–2 mg/hr and concomitant administration of subtherapeutic heparin (targeting an activated partial thromboplastin time [aPTT] 1.25–1.5 times the baseline value).15 However, the concomitant use of heparin with alteplase is problematic in the patient with HITT and acute limb ischemia, as heparin is absolutely contraindicated in this scenario. The clinical literature de712
scribing the use and management of alternative, nonheparin anticoagulants with alteplase during CDT is still very limited.16-18 Here we report the case of an oncology patient with HITT in whom argatroban and CDT with alteplase were used. Case report A 63-year-old Caucasian man (weight, 103.1 kg; height, 184 cm) with a history of amyloid light-chain amyloidosis with renal involvement was undergoing peripheral blood stem cell (PBSC) collection for an autologous stem cell transplant. He was admitted to the emergency department (ED) with syncope and swelling of the face and neck. Of note, the patient had received a right subclavian apheresis catheter 15 days prior to the ED admission in preparation for PBSC collection. Highdose granulocyte colony–stimulating factor (GCSF) therapy had been initiated 12 days prior to admission, and the patient had undergone four daily apheresis sessions starting 9 days prior to admission. Three days prior to ED admission, he was diagnosed with a right upper-extremity DVT at our institution and started on therapeutic anticoagulation with enoxaparin. The patient had been exposed to heparin flushes in the 15 days since placement of the apheresis catheter, and his platelet count had decreased from 222,000 cells/mL to 41,000 cells/mL during that time. Although HIT was included in the differential diagnosis, the patient’s thrombocytopenia was attributed to his apheresis treatments. Other pertinent information in the medical history included hypertension, dyslipidemia, and nephrotic syndrome with light-chain proteinuria. His outpatient medications included enoxaparin 100 mg subcutaneously every 12 hours, aspirin 81 mg daily, furosemide 40 mg twice daily, potassium chloride 20 meq daily, prava statin 40 mg daily, and olmesartan
Am J Health-Syst Pharm—Vol 71 May 1, 2014
20 mg daily. Pertinent laboratory values prior to admission and during hospitalization are presented in Table 1. The patient was admitted to the general medical floor with presumed SVC syndrome. Imaging revealed a new left upper-extremity DVT in the proximal midinternal jugular and subclavian veins, an extensive right upper-extremity DVT extending throughout the venous system to the SVC, and segmental PE in the right lung. Due to concern about potential HIT, an enzyme-linked immunosorbent assay (ELISA) for the HIT antibody and a serotoninrelease assay (SRA) were performed, and the patient was empirically initiated on a continuous i.v. infusion of argatroban (GlaxoSmithKline, Research Triangle Park, NC). The result of the ELISA for HIT antibody was reported as positive (optical density, 3.169; cutoff value, >0.4), as was the result of the SRA. On hospital day 6, the patient experienced brief episodes of loss of consciousness and stiffening during coughing spells. He was transferred to the medical intensive care unit (MICU) on hospital day 7 for the treatment of hypoxic respiratory insufficiency and acute renal failure requiring continuous slow lowefficiency hemodialysis (SLED) and for close hemodynamic monitoring. On hospital day 8, he underwent CDT and percutaneous mechanical thrombectomy, during which he was intubated for airway protection. Alteplase (Activase, Genentech, Inc., South San Francisco, CA) 0.2-mg/mL injection for infusion was prepared by reconstituting 50 mg of the drug in 0.9% sodium chloride injection for a total volume of 250 mL, and equal amounts were instilled into each arm, with a dwell time of approximately 10 minutes. Following CDT, a mechanical thrombectomy was performed and resulted in partial recanalization of the SVC and central veins; thrombosis of bilateral
Am J Health-Syst Pharm—Vol 71 May 1, 2014
a INR = International Normalized Ratio, aPTT = activated partial thromboplastin time, ALT = alanine transaminase, AST = aspartate transaminase, SLED = slow low-efficiency hemodialysis, IHD = intermittent hemodialysis, DVT = deep vein thrombosis, SVC = superior vena cava, MICU = medical intensive care unit, PMT = percutaneous mechanical thrombectomy, CDT = catheter-directed thrombolysis. b First heparin exposure occurred on day –15. c Prior to admission. d Patient receiving argatroban. e Not measured.
IHD Discharged home IHD Transferred to general medical floor IHD Continuous CDT stopped SLED Transferred to MICU None Presented with SVC syndrome None DVT diagnosed
SLED First PMT and CDT
SLED Second PMT, continuous CDT started
8.09 5.81 2.81 1.92 1.55 1.03 1.08
1.75
0.3 0.8 1
