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RESEARCH CORRESPONDENCE Activated partial thromboplastin time overestimates anti-coagulation in left ventricular assist device patients Colleen K. McIlvennan, DNP, ANP,a Robert L. Page II, PharmD, MSPH,b Amrut V. Ambardekar, MD,a Andreas Brieke, MD,a and JoAnn Lindenfeld, MDa From the aDivision of Cardiology, University of Colorado School of Medicine; and the bSchool of Pharmacy, University of Colorado, Aurora, Colorado

Patients with continuous-flow left ventricular assist devices (LVADs) require long-term systemic anti-coagulation after implantation to prevent thrombotic events. Thrombosis of an LVAD may result in cerebrovascular accidents, device exchange or death. Over the past several years, there has been a reported increase in the risk of device thrombosis in the United States, without a clear explanation for the increase.1 Proper anticoagulation management in patients with an LVAD is essential for thrombosis prevention. Unfractionated heparin (UFH) is often used to bridge LVAD patients early after surgical implantation or when oral anti-coagulation is sub-therapeutic. Due to its mechanism of action, the activated partial thromboplastin time (aPTT) reflects the function of heparin’s effects on the intrinsic pathways of the coagulation cascade, whereas the anti-factor Xa (anti-Xa) assay measures heparin’s impact on anti-thrombin.2 The aPTT is currently the most commonly used laboratory test for monitoring UFH. A large number of variables can affect the aPTT, rendering the patient receiving UFH at risk of supra- or sub-therapeutic anticoagulation. Routine monitoring of UFH using the anti-Xa assay has been reported to provide a more accurate reflection of anti-coagulation.2 Since the 1990s, the American College of Chest Physicians and the College of American Pathologists have recommended that aPTT goals be titrated to a corresponding anti-Xa level according to individual institutions. It is currently unknown whether the aPTT and anti-Xa levels reflect the same level of anti-coagulation in LVAD patients. Due to a higher-than-expected LVAD thrombosis rate at our institution, we hypothesized that the aPTT may not adequately reflect the level of anti-coagulation with UFH in LVAD patients; therefore, we simultaneously measured the aPTT and anti-Xa activity in both LVAD recipients and patients admitted with acute decompensated heart failure (ADHF). We performed a prospective, single-center quality improvement project that included all hospitalized patients receiving

UFH who had (1) an LVAD or (2) ADHF on the Advanced Heart Failure Service. Patients were included if they were receiving UFH after device implantation, as bridging therapy for a sub-therapeutic international normalized ratio (INR), or for active thrombosis. Target INR goals for both the HeartMate II (Thoratec Corporation, Pleasanton, CA) and HeartWare HVAD (HeartWare International Inc, Framingham, MA) were 2.0 to 3.0. We obtained simultaneous aPTT and anti-Xa levels after patients were on a stable dose of UFH for a minimum of 6 hours. aPTT and anti-Xa activity levels were determined by standard techniques using Stago reagents. Therapeutic values were locally defined as aPTT of 60 to 90 seconds and anti-Xa of 0.3 to 0.7 U/ml. Each aPTT value and its corresponding anti-Xa level were plotted. The slope representing the relationship between aPTT levels and anti-Xa levels was determined for each population using linear regression models. Analysis of covariance models were used to determine statistical significance between the groups. All analyses were performed using SAS (version 9.3) statistical software (SAS Institute, Inc., Cary, NC). Our study was approved by the institutional review board of the University of Colorado. From February to June 2014, 19 individual patients with durable LVADs and 10 individual patients with ADHF had simultaneous aPTT and anti-Xa levels drawn (Table 1). The ages (mean ⫾ SD) of the groups were 55 ⫾ 11 years and 59 ⫾ 13 years, respectively. Of the patients with durable LVADs, 9 had been implanted o30 days, 15 had a HeartMate II device, and 4 were being treated for an active device thrombosis.

LVAD patients Of the 19 patients with LVADs who had simultaneous aPTT and anti-Xa levels drawn, 10 had therapeutic aPTTs. All 10 of these patients had sub-therapeutic anti-Xa levels. Nine of the 10 patients with therapeutic aPTT levels were taking warfarin, with a mean INR of 1.6. Of the 6 patients with supra-therapeutic aPTT levels, 4 had sub-therapeutic and 2 had therapeutic anti-Xa levels.

ADHF patients Of the 10 patients with ADHF who had simultaneous aPTT and anti-Xa levels drawn, 6 had therapeutic aPTTs. Of these 6 patients, 4 had therapeutic anti-Xa levels, 1 had a sub-therapeutic anti-Xa level and 1 had a supra-therapeutic anti-Xa level. Three of the 6 patients with therapeutic aPTT levels were taking warfarin, with a mean INR of 1.6.

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Research Correspondence Table 1

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Demographics and Anti-coagulation Levels of LVAD and ADHF Cohortsa

LVAD LVAD patients 1 HMII 2 HMII 3 HMII 4 HMII 5 HMII 6 HMII 7 HMII 8 HMII 9 HMII 10 HMII 11 HVAD 12 HVAD 13 HMII 14 HMII 15 HVAD 16 HMII 17 HMII 18 HMII 19 HVAD ADHF patients 1 — 2 — 3 — 4 — 5 — 6 — 7 — 8 — 9 — 10 —

Anti-Xa

aPTT

INR

Warfarinb

LVAD o30 days

Active thrombosisc

Age (years)

Gender

Etiology

o0.1 o0.1 o0.1 0.15 0.28 o0.1 0.22 0.11 0.3 0.19 o0.1 0.18 o0.1 0.43 0.27 0.13 0.26 0.23 0.29

113.0 72.9 47.8 113.3 78.8 34.2 85.1 39.4 128.7 71.4 76.2 70.3 69.2 112.7 64.9 63.1 130.2 183.9 81.6

2.3 1.8 1.2 1.3 1.3 1.3 1.5 1.3 1.7 1.5 1.8 1.9 1.9 3.7 1.3 — 2.6 4.4 1.2

Y Y Y Y N Y Y N Y Y Y Y Y Y Y Y Y Y Y

N N Y Y Y Y N Y N N Y N Y N Y N N N Y

N N N N Y N N N N N N N N Y N N Y Y N

55 63 70 52 54 72 65 53 51 66 59 40 63 50 32 63 57 47 32

F M M M M M F M M M F M M M M M F M M

NICM ICM ICM NICM ICM ICM NICM NICM ICM NICM NICM NICM ICM NICM NICM NICM ICM NICM NICM

0.31 0.16 0.28 0.16 0.24 0.39 1.14 0.47 0.34 0.34

70.5 50.8 59.9 59.4 85.2 80.7 63.5 71.7 97.8 67.0

2 1.1 1.2 1.3 — 1.2 — 1.1 1.8 1.2

Y N N Y Y N N Y Y N

— — — — — — — — — —

N N N N N N N N N N

66 59 62 65 39 59 81 36 60 63

M F M M M M M F F M

NICM NICM NICM NICM ICM ICM ICM NICM NICM ICM

ADHF, acute decompensated heart failure; anti-Xa, anti-factor Xa; aPTT, activated partial thromboplastin time; HMII, HeartMate II; HVAD, HeartWare left ventricular assist device; ICM, ischemic cardiomyopathy; INR, international normalized ratio; LVAD, left ventricular assist device; NICM, non-ischemic cardiomyopathy. a Shaded values ¼ therapeutic aPTT levels (60 to 90 seconds). b No warfarin therapy defined as 47 days from last dose of warfarin. c Thrombosis defined as: LVAD patients ¼ device thrombosis; ADHF patients ¼ venous thrombosis.

Figure 1 compares aPTT to anti-Xa activity for LVAD patients (Figure 1A) and ADHF patients (Figure 1B), and ADHF patients with the removal of one major outlier (Patient 7) (Figure 1C). The outlier patient was an 81-yearold man with ischemic cardiomyopathy, who was being treated for a bacteremia and was managed on concomitant UFH and a glycoprotein IIb/IIIa inhibitor; however, there was no clear cause for the supra-therapeutic anti-Xa level. Comparison between slopes of the line showed: LVAD vs ADHF (with outlier), p ¼ 0.12; and LVAD vs ADHF (without outlier), p ¼ 0.03. Our findings suggest that the aPTT overestimates the level of UFH anti-coagulation in LVAD patients compared with patients without LVADs hospitalized with ADHF. Three possible explanations for this finding include: (1) an effect of acquired von Willebrand’s (VW) syndrome in lowering Factor VIII (FVIII) levels in LVAD patients; (2) under-dosing UFH due to the effect of warfarin on aPTT levels in LVAD patients; and (3) a combination of both.

The presence of acquired VW syndrome in LVAD patients has been reported by a number of investigators.3 The VW factor affects fibrin clot formation by acting as a carrier protein for FVIII. An abnormality in VW factor allows for increased proteolysis of FVIII, resulting in a prolonged aPTT, but with no effect on the anti-Xa activity.4 A defect in VW factor has been reported to occur in virtually all patients with continuous-flow LVADs.3 To our knowledge, FVIII levels in LVAD patients with acquired VW syndrome have not been reported. Warfarin has a small effect on the aPTT, but the effect is magnified in the presence of heparin. It has been estimated that for each increase of 1.0 in the INR, the aPTT increases by 16 seconds.5 However, this does not seem likely to be the sole explanation for our findings, because, even when correcting for this difference in our sample, 7 of the 10 LVAD patients would still have therapeutic aPTT levels with sub-therapeutic anti-Xa levels. All durable LVAD patients require long-term systemic anti-coagulation with wafarin therapy; therefore, the

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The Journal of Heart and Lung Transplantation, Vol 33, No 12, December 2014

Figure 1 Comparison of aPTT with anti-Xa levels in the LVAD and ADHF cohorts. (A) LVAD patients. (B) ADHF patients. (C) ADHF patients with the removal of the major outlier (Patient 7). The central boxed areas in each trace represent therapeutic aPTT levels and anti-Xa levels. ADHF, acute decompensated heart failure; anti-Xa, anti-factor Xa; aPTT, activated partial thromboplastin time; LVAD, left ventricular assist device.

aPTT may be falsely elevated and may lead to insufficient anticoagulation if dosing UFH from aPTT levels. This is a preliminary report in a small number of patients. However, the incidence of thrombosis is high in LVAD patients and all potential causes need to be reported quickly so that they can be investigated in larger numbers and at multiple institutions. Several hypotheses need to be tested in LVAD patients, including: exclusive monitoring of anti-Xa levels (or a combination of anti-Xa and aPTT) and the increased risk of bleeding when monitoring anti-Xa levels. Our results suggest that aPTT levels underestimate anti-coagulation in LVAD patients and monitoring UFH with anti-Xa levels more accurately reflects the level of anti-coagulation.

Disclosure statement The authors have no conflicts of interest to disclose. A.V.A. was supported by a Scientist Development Grant from the American

Gastroparesis is common after lung transplantation and may be ameliorated by botulinum toxin-A injection of the pylorus Nicole Hooft, MD, Michael Smith, MD, Jasmine Huang, MD, Ross Bremner, MD, and Rajat Walia, MD From the St. Joseph’s Hospital and Medical Center, Phoenix Arizona.

Heart Association and by the Boettcher Foundation’s WebbWaring Biomedical Research Program.

References 1. Starling RC, Moazami N, Silvestry SC, et al. Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J Med 2014; 370:33-40. 2. Vandiver JW, Vondracek TG. Antifactor Xa levels versus activated partial thromboplastin time for monitoring unfractionated heparin. Pharmacotherapy 2012;32:546-58. 3. Crow S, Chen D, Milano C, et al. Acquired von Willebrand syndrome in continuous-flow ventricular assist device recipients. Ann Thorac Surg 2010;90:1263-9. 4. Brinkhous KM, Sandberg H, Garris JB, et al. Purified human factor VIII procoagulant protein: comparative hemostatic response after infusions into hemophilic and von Willebrand disease dogs. Proc Natl Acad Sci USA 1985;82:8752-6. 5. Kearon C, Johnston M, Moffat K, et al. Effect of warfarin on activated partial thromboplastin time in patients receiving heparin. Arch Intern Med 1998:1140-3.

Gastroparesis has been demonstrated in the lung transplant population with an incidence between 23% and 91%.1 In addition to pre-transplant medical conditions, lung transplantation itself has been associated with gastroparesis. Specific etiologies include pre-existing lung disease,2 intraoperative vagal nerve injury, and immunosuppression.3 Significant morbidity is associated with gastroparesis. Of primary concern is the increased risk for gastroesophageal reflux disease (GERD) and aspiration, which have been linked to the development of bronchiolitis obliterans syndrome (BOS),

Activated partial thromboplastin time overestimates anti-coagulation in left ventricular assist device patients.

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