Progressive, Fatal Thrombosis Associated With Heparin-Induced Thrombocytopenia After Cardiac Surgery Despite “Therapeutic” Anticoagulation With Argatroban: Potential Role for PTT and ACT Confounding Maureen A. Smythe, PharmD,*† Lisa L. Forsyth, PharmD,*† Theodore E. Warkentin, MD,‡ Marc D. Smith, MD,§ Jo-Ann I. Sheppard, BSc,‡ and Francis Shannon, MD¶
P
ATIENTS WITH heparin-induced thrombocytopenia (HIT) require anticoagulation with a non-heparin anticoagulant such as a parenteral direct thrombin inhibitor (DTI). DTI therapy traditionally is monitored using the activated partial thromboplastin time (aPTT), despite limitations of varying aPTT reagent sensitivity and a flattening of the dose-response curve.1 An emerging issue in the area of DTI monitoring is “PTT confounding,” which is defined as a situation in which an underlying patient-related clinical factor (or factors) results in anticoagulant-related changes to PTT values that are misleading with respect to indicating a patient’s true level of anticoagulation.2 A prolongation in the PTT result can occur with hepatic dysfunction/failure, disseminated intravascular coagulation (DIC), antiphospholipid syndrome, vitamin K antagonist use, hypothermia, and hemodilution.3–8 For patients with acute HIT undergoing cardiopulmonary bypass (CPB), higher DTI doses are required, and the activated coagulation time (ACT) is recommended for monitoring.9 The ACT also is subject to confounding during CPB and extracorporeal membrane oxygenation (ECMO) by hemodilution.10,11 The present case report describes a 36-year-old male, status post-aortic valve replacement, who developed HIT requiring ECMO support resulting in progressive, fatal thrombosis. Subtherapeutic argatroban anticoagulation due to PTT and ACT confounding was the likely cause. CASE REPORT
A 36-year-old male patient underwent an aortic valve replacement (hemisternotomy with bovine pericardial valve) with aortic root and sinus of valsalva enlargement with a bovine pericardial patch. On postoperative day (POD) 4, a heparin infusion was started for left femoral vein deep-vein thrombosis (DVT); testing for HIT antibodies was negative. On POD 10, HIT was suspected based on a new platelet count drop from 145 109/L to 48 109/L that began on POD 8 (Fig 1) and 4Ts score of 8 (based on 66% platelet count fall that began between days 5 and 10 with new thrombosis, described subsequently) in the absence of any other plausible cause. Heparin was discontinued and an argatroban (GlaxoSmithKline, Research Triangle Park, NC) infusion was initiated at 0.8 μg/kg/min. Renal and hepatic function were mildly abnormal; BUN and creatinine of 38 and 1.56 mg/dL, respectively, and bilirubin of 0.5 mg/dL. An upper-extremity DVT was found in the right subclavian and brachial veins and the left subclavian and axillary veins. Vitamin K was given to reverse a single warfarin dose on POD 9. HIT with HIT-associated DIC were suspected; D-dimer 49,999 ng/mL F.E.U. (reference range, o499 ng/mL F.E.U.). The antiplatelet factor 4 enzymeimmunoassay returned positive with an optical density of 1.55
(95% inhibition with high-dose heparin). On POD 11, the patient underwent an emergent embolectomy for a saddle pulmonary embolus. Two large, solid, mature clots were extracted from the right and left main pulmonary arteries along with smaller fragments. The atrial appendage was excised and a thromboembolism adherent to the right atrial wall was debulked. Intraoperative ACTs ranged from 544 seconds to 41005 seconds. The patient was unable to be separated from bypass and venousarterial ECMO was initiated using a heparin-free oxygenator and tubing, with a target aPTT of 45 seconds to 90 seconds and target ACT of 250-300 seconds. Postoperatively, the patient had cardiogenic shock, acute kidney injury, shock liver, coagulase-negative bacteremia, and hypoxic hypovolemic encephalopathy. The patient’s fibrinogen was 52 mg/dL, with a platelet count of 25 109/L (both findings consistent with DIC). On POD 11, the argatroban infusion was held for 35 hours for supratherapeutic clotting time results, an aPTT 4100 seconds and ACT results ranging from 319 to 41005 seconds. The patient’s oxygenation and right ventricular function improved on ECMO. On POD 13, two additional argatroban hold periods were required; the resulting argatroban infusion rate was 0.1 μg/kg/minute (82% dose reduction). On POD 14, a send-out serotonin-release assay drawn on POD 10 returned positive. Decannulation was performed on argatroban because of the acute HIT. No residual clot was visualized intraoperatively. Thromboelastography results revealed normal clot formation [reaction time (time to initial fibrin formation, R), time to clot formation (K) and rate of clot formation (angle)] despite an ACT of 240 seconds and an aPTT of 59.4 seconds. Post-decannulation the patient’s right ventricular function was excellent, with an oxygen saturation of 100%. On POD 14, significant progression of both the right and left upperextremity DVT were noted. On POD 15, the argatroban infusion was held again for an aPTT of 107.5 seconds. Multiple organ
From the *Department of Pharmaceutical Services, Beaumont Hospital, Royal Oak, MI; †Department of Pharmacy Practice, Wayne State University, Detroit, MI; ‡Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada; §Department of Clinical Pathology, Beaumont Hospital, Royal Oak, MI; and ¶Cardiovascular Research and Quality Programs, Ernst Cardiovascular Center, Beaumont Hospital, Royal Oak, MI. Address reprint requests to Maureen A. Smythe, PharmD, Department of Pharmacy Practice, Wayne State University, 259 Mack Avenue, Suite 2190, Detroit, MI 28202. E-mail: [email protected] © 2015 Elsevier Inc. All rights reserved. 1053-0770/2602-0033$36.00/0 http://dx.doi.org/10.1053/j.jvca.2014.04.029 Key words: heparin, argatroban, ACT, PTT confounding, heparininduced thrombocytopenia
Journal of Cardiothoracic and Vascular Anesthesia, Vol 29, No 5 (October), 2015: pp 1319–1321
1319
1320
SMYTHE ET AL
TEG normal day 14, indicating underanticoagulation
To OR for embolectomy
Heparin PTT therapeutic range
50
48 s
UFH (U/hr)
300
Period of PTT and ACT confounding UFH 3,000-U boluses
UFH interrupted for procedures (likely subtherapeutic days 4-8)
0 EIA & SRA = Pos
EIA = Neg
100
Argatroban: repeated dose interruptions/reductions 2o to PTT confounding (likely subtherapeutic days 13-15)
UFH 5,000 U sc x 3
1000
150
500
59.4
UFH 40,000 U (CPB) 2000
74.1
71 s
25 200
900 700
Saddle PE, Rt atrial thrombus, Rt UE DVT, Lt UE DVT
75
>124
100
ACT, s
Lt LE DVT
100 PTT, s
300 200 100 0
Fib (mg/dL)
>1005 >124
125
Platelet count (x10-9/L)
>9 307
2.0 1.0
Argatroban (mcg/kg/min)
INR
>9
7 5 3 1
0 Preterminal progressive venous thrombosis: (a) Day 14: Rt IJ DVT; progressive Rt UE DVT (b) Day 14: Progressive Lt UE DVT (c) Day 15: Enlarging Rt atrial thrombus
Onset of HIT (Day 8) Death (biventricular failure)
Cardiac surgery (Aortic valve replacement)
50
Warfarin Vit K 5 mg 5 mg
0 0
2
Platelet transfusion (2 units)
4 6 8 10 12 Days after immunizing heparin exposure (cardiac surgery)
14
16
Fig 1. PTT and ACT confounding during argatroban therapy for HIT. The diagnosis of HIT was made on postoperative day 10 after multiple thrombotic events. Argatroban was initiated and continued in the presence of 3 PTT and ACT confounders, including shock liver, disseminated intravascular coagulation, and extracorporeal membrane oxygenation. Supratherapeutic clotting time tests resulted in serial argatroban infusion interruptions and dose reductions, which were followed by progressive thrombosis. Thromboelastography performed on postoperative day 14 supported the presence of ACT and PTT confounding. Abbreviations: ACT, activated clotting time; aPTT, activated partial thromboplastin time; DVT, deep vein thrombosis; EIA, enzyme immunoassay; Fib, fibrinogen; HIT, heparin-induced thrombocytopenia; IJ, internal jugular; INR, international normalized ratio; LE, lower-extremity; Lt, left; Neg, negative; OR, operating room; PE, pulmonary embolus; Pos, positive; PTT, partial thromboplastin time; TEG, thromboelastography; Rt, right; SRA serotonin release assay; U, units; UE, upperextremity; UFH, unfractionated heparin; Vit K, vitamin K.
failure progressed. During sternal closure, an enlarging right atrial thrombus was found (2 cm wide by 4 cm long) with prolapse into the orifice of the tricuspid valve. An open right atriotomy on partial bypass was performed. The patient developed biventricular failure, culminating in pulseless electrical activity and open chest-cardiopulmonary resuscitation. He could not be resuscitated and died of biventricular failure. DISCUSSION
Global anticoagulant assays such as the aPTT and the ACT are recommended for DTI monitoring despite their known limitations.1 The aPTT can be prolonged by many patientspecific factors that are common in the postoperative period, including liver dysfunction, DIC, hypothermia, and hemodilution.2,8 Although the ACT is less susceptible to hemodilution compared with the aPTT, it can be prolonged by thrombocytopenia, hypothermia, antiplatelet therapy, and fibrinogen
depletion.12 Non drug-induced elevations in the PTT and ACT can lead to systematic anticoagulant underdosing, which can place patients with HIT, an extreme hypercoagulable condition, at high risk for adverse outcomes. Progressive thrombosis occurred in this patient as a result of argatroban under-anticoagulation from PTT and ACT confounding. DIC, shock liver, and ECMO (hemodilution and low fibrinogen) were the primary confounders. A fibrinogen concentration of 52 mg/dL supported DIC as a confounder as in vitro testing in the health-system laboratory revealed the fibrinogen assay was relatively insensitive to increasing argatroban concentrations. A normal reaction time on thromboeslatography in the presence of therapeutic clotting time tests was consistent with PTT and ACT confounding. The temporal events of a significant anticoagulant dose reduction on POD 13 followed by progressive thrombosis on PODs 14 and 15 were congruent with argatroban underdosing.
1321
FATAL THROMBOSIS WITH HIT
Alternatives to the aPTT and ACT for DTI monitoring include a dilute thrombin time, the ecarin clotting time, or an anti-IIa assay.1,13 Although both the dilute thrombin time and the ecarin clotting time assays would be unaffected by shock liver, each would require the addition of normal pooled plasma (or appropriate coagulation factors) to avoid prolongation due to hypofibrinogenemia.14 The anti-IIa assay would overcome the issue of confounders, and successful use has been reported.15 The limited availability of this test, however, remains an issue. If available, a correlation of the anti-IIa result to an ACT may allow for the creation of a management strategy for times during which the anti-IIa assay may not be available. This pattern observed in the present case—progressive thrombosis that occurred during serial DTI dose interruptions/reductions
triggered by persistence of supratherapeutic PTT and/or ACT values—is the reported clinical picture of anticoagulant treatment failure caused by the phenomenon of PTT and/or ACT confounding.2,4,7 In cases of PTT or ACT confounding, alternative anticoagulation monitoring strategies such as an anti-IIa assay or a dilute thrombin time or ecarin clotting time using normal pooled plasma (or appropriate coagulation factors) should be explored if available. ACKNOWLEDGMENT
The authors thank Caridad Canlas, MT(ASCP), Department of Clinical Pathology, Beaumont Hospital, Royal Oak, MI, for performing the in-vitro argatroban-fibrinogen dose-response curve.
REFERENCES 1. Ivandic B, Zorn M: Monitoring of the anticoagulants argatroban and lepirudin: A comparison of laboratory methods. Clin Appl Thromb Hemost 17:549-555, 2011 2. Warkentin TE: Anticoagulant failure in coagulopathic patients: PTT confounding and other pitfalls. Expert Opin Drug Saf 13:25-43, 2014 3. Jaax ME, Greinacher A: Management of heparin-induced thrombocytopenia. Expert Opin Pharmacother 13:987-1006, 2012 4. Warkentin TE: Agents for the treatment of heparin-induced thrombocytopenia. Hematol Oncol Clinics North Am 24:755-775, ix, 2010 5. Warkentin TE: HITlights: A career perspective on heparin-induced thrombocytopenia. Am J Hematol 87(suppl):S92-S99, 2012 (suppl) 6. Greinacher A: Lepirudin for the treatment of heparin induced thrombocytopenia, In: Warkentin TE, Greinacher A, eds. HeparinInduced Thrombocytopenia. Fourth Edition. New York, NY: Informa Healthcare USA, 2008, pp. 345-378 7. Linkins LA, Warkentin TE: Heparin-induced thrombocytopenia: Real-world issues. Semin Thromb Hemost 37:653-663, 2011 8. Darlington DN, Kremenevskiy I, Pusateri AE, et al: Effects of in vitro hemodilution, hypothermia and rFVIIa addition on coagulation in human blood. Int J Burns Trauma 2:42-50, 2012
9. Sniecinski RM, Chandler WL: Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 113:1319-1333, 2011 10. Oliver WC: Anticoagulation and coagulation management for ECMO. Semin Cardiothorac Vasc Anesth 13:154-175, 2009 11. Owings JT, Pollock ME, Gosselin RC, et al: Anticoagulation of children undergoing cardiopulmonary bypass is overestimated by current monitoring techniques. Arch Surg 135:1042-1047, 2000 12. Finley A, Greenberg C: Review article: Heparin sensitivity and resistance: Management during cardiopulmonary bypass. Anesth Analg 116:1210-1222, 2013 13. Wanat MA, Hart SR, Putney D, et al: Alternative monitoring of argatroban using plasma-diluted thrombin time. Ann Pharmacother 47: e18, 2013 14. Choi TS, Khan AI, Greilich PE, et al: Modified plasma-based ecarin clotting time assay for monitoring of recombinant hirudin during cardiac surgery. Am J Clin Pathol 125:290-295, 2006 15. Cornell T, Wyrick P, Fleming G, et al: A case series describing the use of argatroban in patients on extracorporeal circulation. ASAIO J 53:460-463, 2007
P
ATIENTS WITH heparin-induced thrombocytopenia (HIT) require anticoagulation with a non-heparin anticoagulant such as a parenteral direct thrombin inhibitor (DTI). DTI therapy traditionally is monitored using the activated partial thromboplastin time (aPTT), despite limitations of varying aPTT reagent sensitivity and a flattening of the dose-response curve.1 An emerging issue in the area of DTI monitoring is “PTT confounding,” which is defined as a situation in which an underlying patient-related clinical factor (or factors) results in anticoagulant-related changes to PTT values that are misleading with respect to indicating a patient’s true level of anticoagulation.2 A prolongation in the PTT result can occur with hepatic dysfunction/failure, disseminated intravascular coagulation (DIC), antiphospholipid syndrome, vitamin K antagonist use, hypothermia, and hemodilution.3–8 For patients with acute HIT undergoing cardiopulmonary bypass (CPB), higher DTI doses are required, and the activated coagulation time (ACT) is recommended for monitoring.9 The ACT also is subject to confounding during CPB and extracorporeal membrane oxygenation (ECMO) by hemodilution.10,11 The present case report describes a 36-year-old male, status post-aortic valve replacement, who developed HIT requiring ECMO support resulting in progressive, fatal thrombosis. Subtherapeutic argatroban anticoagulation due to PTT and ACT confounding was the likely cause. CASE REPORT
A 36-year-old male patient underwent an aortic valve replacement (hemisternotomy with bovine pericardial valve) with aortic root and sinus of valsalva enlargement with a bovine pericardial patch. On postoperative day (POD) 4, a heparin infusion was started for left femoral vein deep-vein thrombosis (DVT); testing for HIT antibodies was negative. On POD 10, HIT was suspected based on a new platelet count drop from 145 109/L to 48 109/L that began on POD 8 (Fig 1) and 4Ts score of 8 (based on 66% platelet count fall that began between days 5 and 10 with new thrombosis, described subsequently) in the absence of any other plausible cause. Heparin was discontinued and an argatroban (GlaxoSmithKline, Research Triangle Park, NC) infusion was initiated at 0.8 μg/kg/min. Renal and hepatic function were mildly abnormal; BUN and creatinine of 38 and 1.56 mg/dL, respectively, and bilirubin of 0.5 mg/dL. An upper-extremity DVT was found in the right subclavian and brachial veins and the left subclavian and axillary veins. Vitamin K was given to reverse a single warfarin dose on POD 9. HIT with HIT-associated DIC were suspected; D-dimer 49,999 ng/mL F.E.U. (reference range, o499 ng/mL F.E.U.). The antiplatelet factor 4 enzymeimmunoassay returned positive with an optical density of 1.55
(95% inhibition with high-dose heparin). On POD 11, the patient underwent an emergent embolectomy for a saddle pulmonary embolus. Two large, solid, mature clots were extracted from the right and left main pulmonary arteries along with smaller fragments. The atrial appendage was excised and a thromboembolism adherent to the right atrial wall was debulked. Intraoperative ACTs ranged from 544 seconds to 41005 seconds. The patient was unable to be separated from bypass and venousarterial ECMO was initiated using a heparin-free oxygenator and tubing, with a target aPTT of 45 seconds to 90 seconds and target ACT of 250-300 seconds. Postoperatively, the patient had cardiogenic shock, acute kidney injury, shock liver, coagulase-negative bacteremia, and hypoxic hypovolemic encephalopathy. The patient’s fibrinogen was 52 mg/dL, with a platelet count of 25 109/L (both findings consistent with DIC). On POD 11, the argatroban infusion was held for 35 hours for supratherapeutic clotting time results, an aPTT 4100 seconds and ACT results ranging from 319 to 41005 seconds. The patient’s oxygenation and right ventricular function improved on ECMO. On POD 13, two additional argatroban hold periods were required; the resulting argatroban infusion rate was 0.1 μg/kg/minute (82% dose reduction). On POD 14, a send-out serotonin-release assay drawn on POD 10 returned positive. Decannulation was performed on argatroban because of the acute HIT. No residual clot was visualized intraoperatively. Thromboelastography results revealed normal clot formation [reaction time (time to initial fibrin formation, R), time to clot formation (K) and rate of clot formation (angle)] despite an ACT of 240 seconds and an aPTT of 59.4 seconds. Post-decannulation the patient’s right ventricular function was excellent, with an oxygen saturation of 100%. On POD 14, significant progression of both the right and left upperextremity DVT were noted. On POD 15, the argatroban infusion was held again for an aPTT of 107.5 seconds. Multiple organ
From the *Department of Pharmaceutical Services, Beaumont Hospital, Royal Oak, MI; †Department of Pharmacy Practice, Wayne State University, Detroit, MI; ‡Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada; §Department of Clinical Pathology, Beaumont Hospital, Royal Oak, MI; and ¶Cardiovascular Research and Quality Programs, Ernst Cardiovascular Center, Beaumont Hospital, Royal Oak, MI. Address reprint requests to Maureen A. Smythe, PharmD, Department of Pharmacy Practice, Wayne State University, 259 Mack Avenue, Suite 2190, Detroit, MI 28202. E-mail: [email protected] © 2015 Elsevier Inc. All rights reserved. 1053-0770/2602-0033$36.00/0 http://dx.doi.org/10.1053/j.jvca.2014.04.029 Key words: heparin, argatroban, ACT, PTT confounding, heparininduced thrombocytopenia
Journal of Cardiothoracic and Vascular Anesthesia, Vol 29, No 5 (October), 2015: pp 1319–1321
1319
1320
SMYTHE ET AL
TEG normal day 14, indicating underanticoagulation
To OR for embolectomy
Heparin PTT therapeutic range
50
48 s
UFH (U/hr)
300
Period of PTT and ACT confounding UFH 3,000-U boluses
UFH interrupted for procedures (likely subtherapeutic days 4-8)
0 EIA & SRA = Pos
EIA = Neg
100
Argatroban: repeated dose interruptions/reductions 2o to PTT confounding (likely subtherapeutic days 13-15)
UFH 5,000 U sc x 3
1000
150
500
59.4
UFH 40,000 U (CPB) 2000
74.1
71 s
25 200
900 700
Saddle PE, Rt atrial thrombus, Rt UE DVT, Lt UE DVT
75
>124
100
ACT, s
Lt LE DVT
100 PTT, s
300 200 100 0
Fib (mg/dL)
>1005 >124
125
Platelet count (x10-9/L)
>9 307
2.0 1.0
Argatroban (mcg/kg/min)
INR
>9
7 5 3 1
0 Preterminal progressive venous thrombosis: (a) Day 14: Rt IJ DVT; progressive Rt UE DVT (b) Day 14: Progressive Lt UE DVT (c) Day 15: Enlarging Rt atrial thrombus
Onset of HIT (Day 8) Death (biventricular failure)
Cardiac surgery (Aortic valve replacement)
50
Warfarin Vit K 5 mg 5 mg
0 0
2
Platelet transfusion (2 units)
4 6 8 10 12 Days after immunizing heparin exposure (cardiac surgery)
14
16
Fig 1. PTT and ACT confounding during argatroban therapy for HIT. The diagnosis of HIT was made on postoperative day 10 after multiple thrombotic events. Argatroban was initiated and continued in the presence of 3 PTT and ACT confounders, including shock liver, disseminated intravascular coagulation, and extracorporeal membrane oxygenation. Supratherapeutic clotting time tests resulted in serial argatroban infusion interruptions and dose reductions, which were followed by progressive thrombosis. Thromboelastography performed on postoperative day 14 supported the presence of ACT and PTT confounding. Abbreviations: ACT, activated clotting time; aPTT, activated partial thromboplastin time; DVT, deep vein thrombosis; EIA, enzyme immunoassay; Fib, fibrinogen; HIT, heparin-induced thrombocytopenia; IJ, internal jugular; INR, international normalized ratio; LE, lower-extremity; Lt, left; Neg, negative; OR, operating room; PE, pulmonary embolus; Pos, positive; PTT, partial thromboplastin time; TEG, thromboelastography; Rt, right; SRA serotonin release assay; U, units; UE, upperextremity; UFH, unfractionated heparin; Vit K, vitamin K.
failure progressed. During sternal closure, an enlarging right atrial thrombus was found (2 cm wide by 4 cm long) with prolapse into the orifice of the tricuspid valve. An open right atriotomy on partial bypass was performed. The patient developed biventricular failure, culminating in pulseless electrical activity and open chest-cardiopulmonary resuscitation. He could not be resuscitated and died of biventricular failure. DISCUSSION
Global anticoagulant assays such as the aPTT and the ACT are recommended for DTI monitoring despite their known limitations.1 The aPTT can be prolonged by many patientspecific factors that are common in the postoperative period, including liver dysfunction, DIC, hypothermia, and hemodilution.2,8 Although the ACT is less susceptible to hemodilution compared with the aPTT, it can be prolonged by thrombocytopenia, hypothermia, antiplatelet therapy, and fibrinogen
depletion.12 Non drug-induced elevations in the PTT and ACT can lead to systematic anticoagulant underdosing, which can place patients with HIT, an extreme hypercoagulable condition, at high risk for adverse outcomes. Progressive thrombosis occurred in this patient as a result of argatroban under-anticoagulation from PTT and ACT confounding. DIC, shock liver, and ECMO (hemodilution and low fibrinogen) were the primary confounders. A fibrinogen concentration of 52 mg/dL supported DIC as a confounder as in vitro testing in the health-system laboratory revealed the fibrinogen assay was relatively insensitive to increasing argatroban concentrations. A normal reaction time on thromboeslatography in the presence of therapeutic clotting time tests was consistent with PTT and ACT confounding. The temporal events of a significant anticoagulant dose reduction on POD 13 followed by progressive thrombosis on PODs 14 and 15 were congruent with argatroban underdosing.
1321
FATAL THROMBOSIS WITH HIT
Alternatives to the aPTT and ACT for DTI monitoring include a dilute thrombin time, the ecarin clotting time, or an anti-IIa assay.1,13 Although both the dilute thrombin time and the ecarin clotting time assays would be unaffected by shock liver, each would require the addition of normal pooled plasma (or appropriate coagulation factors) to avoid prolongation due to hypofibrinogenemia.14 The anti-IIa assay would overcome the issue of confounders, and successful use has been reported.15 The limited availability of this test, however, remains an issue. If available, a correlation of the anti-IIa result to an ACT may allow for the creation of a management strategy for times during which the anti-IIa assay may not be available. This pattern observed in the present case—progressive thrombosis that occurred during serial DTI dose interruptions/reductions
triggered by persistence of supratherapeutic PTT and/or ACT values—is the reported clinical picture of anticoagulant treatment failure caused by the phenomenon of PTT and/or ACT confounding.2,4,7 In cases of PTT or ACT confounding, alternative anticoagulation monitoring strategies such as an anti-IIa assay or a dilute thrombin time or ecarin clotting time using normal pooled plasma (or appropriate coagulation factors) should be explored if available. ACKNOWLEDGMENT
The authors thank Caridad Canlas, MT(ASCP), Department of Clinical Pathology, Beaumont Hospital, Royal Oak, MI, for performing the in-vitro argatroban-fibrinogen dose-response curve.
REFERENCES 1. Ivandic B, Zorn M: Monitoring of the anticoagulants argatroban and lepirudin: A comparison of laboratory methods. Clin Appl Thromb Hemost 17:549-555, 2011 2. Warkentin TE: Anticoagulant failure in coagulopathic patients: PTT confounding and other pitfalls. Expert Opin Drug Saf 13:25-43, 2014 3. Jaax ME, Greinacher A: Management of heparin-induced thrombocytopenia. Expert Opin Pharmacother 13:987-1006, 2012 4. Warkentin TE: Agents for the treatment of heparin-induced thrombocytopenia. Hematol Oncol Clinics North Am 24:755-775, ix, 2010 5. Warkentin TE: HITlights: A career perspective on heparin-induced thrombocytopenia. Am J Hematol 87(suppl):S92-S99, 2012 (suppl) 6. Greinacher A: Lepirudin for the treatment of heparin induced thrombocytopenia, In: Warkentin TE, Greinacher A, eds. HeparinInduced Thrombocytopenia. Fourth Edition. New York, NY: Informa Healthcare USA, 2008, pp. 345-378 7. Linkins LA, Warkentin TE: Heparin-induced thrombocytopenia: Real-world issues. Semin Thromb Hemost 37:653-663, 2011 8. Darlington DN, Kremenevskiy I, Pusateri AE, et al: Effects of in vitro hemodilution, hypothermia and rFVIIa addition on coagulation in human blood. Int J Burns Trauma 2:42-50, 2012
9. Sniecinski RM, Chandler WL: Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 113:1319-1333, 2011 10. Oliver WC: Anticoagulation and coagulation management for ECMO. Semin Cardiothorac Vasc Anesth 13:154-175, 2009 11. Owings JT, Pollock ME, Gosselin RC, et al: Anticoagulation of children undergoing cardiopulmonary bypass is overestimated by current monitoring techniques. Arch Surg 135:1042-1047, 2000 12. Finley A, Greenberg C: Review article: Heparin sensitivity and resistance: Management during cardiopulmonary bypass. Anesth Analg 116:1210-1222, 2013 13. Wanat MA, Hart SR, Putney D, et al: Alternative monitoring of argatroban using plasma-diluted thrombin time. Ann Pharmacother 47: e18, 2013 14. Choi TS, Khan AI, Greilich PE, et al: Modified plasma-based ecarin clotting time assay for monitoring of recombinant hirudin during cardiac surgery. Am J Clin Pathol 125:290-295, 2006 15. Cornell T, Wyrick P, Fleming G, et al: A case series describing the use of argatroban in patients on extracorporeal circulation. ASAIO J 53:460-463, 2007
