Laboratory assessment of warfarin reversal with global coagulation tests versus international normalized ratio in patients with intracranial bleeding.

Original article 443

Laboratory assessment of warfarin reversal with global coagulation tests versus international normalized ratio in patients with intracranial bleeding Stacy A. Voilsa, Erika J. Martinb, Bassem M. Mohammedb,c, Ahmad Bayrleed and Donald F. Brophyb We assess the in-vivo relationship between international normalized ratio (INR) and global coagulation tests in patients with life-threatening bleeding who received prothrombin complex concentrate (PCC) for warfarin reversal. This was a prospective pilot study in adult patients with intracranial bleeding related to anticoagulation with warfarin. Thromboelastography (TEG), thrombin generation parameters and INR were assessed at baseline, 30 min, 2 and 24 h after PCC. Changes in laboratory parameters and relationship between INR and global coagulation tests were assessed over time. Eight patients mean [standard deviation (SD)] age 72 (16) were included and received mean (SD) dose of PCC 24 (5) units/kg. Four patients died during the study, all with INR values more than 1.5 thirty minutes after PCC. Mean (SD) INR was 3.0 (1.3) and decreased significantly to 1.8 (0.48) thirty minutes after PCC (P < 0.01). Baseline endogenous thrombin potential and thrombin peak were 890 nmol/min and 123 nmol and increased significantly to 1943 nmol/min (P < 0.01) and 301 nmol (P < 0.01) 30 min after PCC administration. Reaction (R)-time decreased significantly (P U 0.02), and maximum amplitude and overall coagulation index (CI) significantly increased during treatment (P < 0.01, respectively). Thrombin generation and TEG values corrected after PCC administration; however, INR did not

Introduction In patients with warfarin-related intracranial hemorrhage, rapid reversal of anticoagulation may decrease hematoma growth and allow for invasive procedures or neurosurgery. Although monitoring of the prothrombin time (PT)/international normalized ratio (INR) is recommended to assess the adequacy of warfarin reversal [1], these approaches have significant limitations. First, the PT/INR test has limited correlation to bleeding [2–5]. This assay uses supraphysiological concentrations of tissue factor (TF) and phospholipids; thus, when prothrombin complex concentrates (PCC) are used, the high concentration of TF and clotting factors (particularly FVII) cause an abrupt decrease in PT/INR. Second, the PT/INR only describes the initiation phase of coagulation, thus, minute amounts of thrombin (approximately 4%) are needed to initiate clotting. Despite clotting in the sample, 96% of thrombin remains yet to be generated [6]. Consequently, PCC administration may correct the INR rapidly even in the

0957-5235 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.

fully correct. Patients that died tended to be older with prolonged INR values across the study period. INR and TEG values correlated well with thrombin generation before administration of PCC, but this relationship was lost afterward. Blood Coagul Fibrinolysis 26:443–447 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.

Blood Coagulation and Fibrinolysis 2015, 26:443–447 Keywords: anticoagulant, factor IX complex, hemostasis, intracerebral hemorrhage, prothrombin complex concentrate, vitamin K antagonist, warfarin a Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, Florida, bCoagulation Advancement Laboratory, Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, Virginia, USA, cFaculty of Pharmacy, Department of Clinical Pharmacy, Cairo University, Cairo, Egypt and d Neuroscience Intensive Care Unit, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA

Correspondence to Stacy A. Voils, PharmD, MSc, BCPS, Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, 1225 Center Drive, HPNP Bldg, Room 3315, PO Box 100486, Gainesville, FL 32610-0486, USA Tel: +1 352 294 5276; fax: +1 352 273 6242; e-mail: [email protected] Received 3 September 2014 Revised 15 December 2014 Accepted 5 January 2015

absence of a hemostatic effect [7]. This phenomenon has been previously shown with recombinant FVIIa [8]. Global coagulation tests such as thromboelastography (TEG) and the thrombin generation assay (TGA) have been suggested as alternatives to PT/INR to assess anticoagulation reversal. TEG provides a total picture of whole blood clotting dynamics from clot initiation through fibrinolysis. The TGA produces a thrombin generation profile and uses a physiologic concentration of TF that may provide a more accurate assessment of coagulation [7,9]. To our knowledge, this is the first case-series to report anticoagulation reversal in patients with warfarin-related intracranial hemorrhage by assessing in-vivo coagulation using global coagulation assays. The objectives of this study were to assess the effect of PCC administration on global laboratory markers of hemostasis, and to determine the relationships between INR, TEG and TGA parameters.

DOI:10.1097/MBC.0000000000000270

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

444 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 4

Methods This was a prospective case-series of eight patients admitted to the neurosurgery ICU at Virginia Commonwealth University (VCU) Health System, an 865-bed academic medical center. Consecutive patients with intracranial bleeding that presented between July 2012 and May 2013 were included in the study if they were at least 18 years of age and received PCC administration for warfarin reversal. Prisoners, hemophiliacs and pregnant patients were excluded. The study was approved by the local investigational review board with an initial waiver of informed consent due to the emergent nature of the intervention. Patients or caregivers were informed of the study as soon as possible and given the opportunity to opt out. Study intervention

Prothrombin complex concentrate (Profilnine, Grifols Pharmaceuticals, Los Angeles, California, USA), a three-factor PCC containing factor II, factor IX, factor X, and low levels of factor VII, was administered within 4 h of injury at the discretion of the treating physician. Approximately 10 ml blood samples were collected from each patient using minimum stasis through a 21-gauge butterfly needle/tubing set into 3.2% (0.105 mol l1) citrated Vacutainer tubes (Becton– Dickinson, Franklin Lakes, New Jersey, USA) at baseline, 30 min, 2 and 24 h following PCC administration. Samples were immediately transported to the hemostasis laboratory where coagulation status was assessed by INR and TEG analysis. Platelet poor plasma (PPP) for TGA analysis was obtained by centrifugation at 2500 g for 10 min at room temperature, and then frozen at 808C. General demographics were collected, including age, weight, type and location of injury, surgical procedure, amount and type of blood products received, and clinical outcome. Global coagulation assays

TEG was conducted on whole blood samples using the TEG 5000 Hemostasis Analyzer (Haemoscope Corporation, Niles, Illinois, USA) using kaolin, buffered stabilizers and phospholipids per manufacturer’s instructions. Reported values include the reaction time (R-time), kinetics time (K-time), maximum amplitude (MA), and coagulation index (CI). Briefly, the R-time reflects the time to clotting onset (minutes); the K-time reflects clot propagation (minutes); the MA reflects final clot strength (mm), and the CI is an overall assessment of coagulation status. The reference ranges for R, K, maximum amplitude and CI are 3– 8 min, 1–3 min, 51–69 mm, and 3 to þ3, respectively [10]. The kinetics of thrombin generation were assessed in PPP by measuring the cleavage of the fluorogenic substrate Z-Gly-Gly-Arg-AMC according to the methods described by Hemker et al. [11]. Tissue factor (PPP reagent, Thrombinoscope BV, Maastricht, the Netherlands) and PPP were pipetted in triplicate into 96-well round-bottom microtitre plates (Immulon 2HB plate; Diagnostica Stago, Parsippany, New Jersey, USA). The

final concentration of tissue factor was 5 pmol/l. Thrombin generation was calculated using the Calibrated Automated Thrombogram software version v.5.0.0.742 (CAT; Thrombinoscope BV). Thrombin generation lag time (T-lag), peak thrombin concentration and endogenous thrombin potential (ETP) were reported. Statistical analysis

Demographic data are reported using descriptive statistics with categorical data presented as frequencies/percentages and continuous data presented as mean [standard deviation (SD)] for normally distributed data, and median (interquartile range) for skewed data. Normality of continuous data was assessed through visual inspection of normal quantile plots. Repeated measures analysis of variance (ANOVA) modeling was used to analyze intrapatient laboratory values over time. Linear regression was used to assess the relationship between PT, TEG values and thrombin generation tests at each time point. Data were analyzed using JMP version 10.0.2 and SAS version 9.3 (SAS Institute, Cary, North Carolina, USA).

Results The demographics for the eight patients are shown in Table 1. The median (interquartile range) Glasgow Coma Scale was 13.5 (11–15) indicating mild cognitive deficits. The most common indication for anticoagulation with warfarin was atrial fibrillation; subdural hematoma was the most common intracranial lesion. In addition to PCC, all patients received 10 mg of intravenous vitamin K and three patients received fresh frozen plasma (FFP). Clinical characteristics

Four patients (50%) in the study died during hospitalization. Three of the four patients were aged 69, 83 and 85, respectively, and two of these patients received concomitant FFP. Those who died tended to have higher baseline INRs and all had INR values more than 1.5 thirty minutes following PCC. They also tended to have lower thrombin peak and ETP, and longer R values over time. Both patients (patients 5 and 6) who were receiving concomitant aspirin therapy died. The individual results for each patient are provided in Table 2. Change in international normalized ratio and thrombin generation parameters

Figure 1 panels a, c, and d depict the changes in INR, peak thrombin and ETP over the 24 h interval. Lag time did not change significantly from baseline at any time point. Change in thromboelastography parameters

Figure 1 panel b depicts the change in R-time over the 24 h interval. Mean (SD) maximum amplitude increased from 64.8 (4.4) mm at baseline to 71.5 (4.9) (P < 0.01), 68.8 (6.9) (P ¼ 0.14), and 66.4 (7.4) mm (P ¼ 0.72) at 30 min, 2 and 24 h after PCC. The mean CI increased from 2.8 (4.8) at baseline to 2.7 (1.4) (P ¼ 0.02), 0.9 (1.1)


Global tests for warfarin reversal following prothrombin complex concentrate Voils et al. 445

Table 1

Baseline characteristics

Age (year), mean (SD) Male sex, n (%) Weight (kg), mean (SD) GCS, median (IQR)

72 4 84 13.5

Admitting diagnosis, n (%)a SDH ICH IVH SAH

5 3 1 1

Medical history, n (%) Atrial fibrillation Hypertension Aspirin use, n (%) INR, median (IQR) Platelet count 109/l, mean (SD)

5 7 2 1.7 213

PCC dose Total units, median (IQR) Units/kg, mean (SD)

(16) (50) (24) (11–15)

(63) (38) (13) (13)

(63) (88) (25) (1.4–2.2) (76)

2105 (1430–2345) 24 (5)

Other hemostasis interventions, n (%) Vitamin K FFP Surgery

8 (100) 3 (38) 2 (25)

FFP, fresh frozen plasma; GCS, Glasgow Coma Scale score; ICH, intracerebral hemorrhage; INR, international normalized ratio; IQR, interquartile range; IVH, intraventricular hemorrhage; PCC, prothrombin complex concentrate; SAH, subarachnoid hemorrhage; SD, standard deviation; SDH, subdural hematoma. a Numbers total more than eight because some patients had more than one admitting diagnosis.

(P ¼ 0.23), and 0.37 (4.0) (P ¼ 0.49) at 30 min, 2 and 24 h after PCC. K-time was not significantly different from baseline at any time point after PCC administration.

(r ¼ 0.91, P < 0.01) and ETP (r ¼ 0.84, P < 0.01), and a significant positive correlation between INR and lag time (r ¼ 0.93, P < 0.001). Following PCC administration, INR was not significantly associated with any thrombin generation parameter at any time point, with the exception of a significant positive correlation between PT and lag time at 30 min (r ¼ 0.83, P ¼ 0.01). Relationships between thromboelastography parameters and thrombin generation

Prior to administration of PCC, there was a significant negative correlation for R-time with ETP (r ¼ 0.71, P ¼ 0.05) and thrombin peak (r ¼ 0.75, P ¼ 0.03), and a significant positive correlation between R-time and lag time (r ¼ 0.94, P < 0.01). After PCC administration, there was no significant association between R-time and any thrombin generation parameter at any time point, with the exception of thrombin peak at 24 h (r ¼ 0.84, P ¼ 0.02). At baseline, there was a significant negative correlation between K-time and thrombin peak (r ¼ 0.74, P ¼ 0.04), a significant positive correlation between K-time and lag time (r ¼ 0.97, P < 0.01), and no significant association between K-time and ETP (r ¼ 0.66, P ¼ 0.07). Following PCC administration, there was no significant relationship between K-time and any thrombin generation parameter at any time point, with the exception of thrombin peak at 24 h (r ¼ 0.91, P < 0.01). Maximum amplitude was not significantly associated with any thrombin generation parameter at any time point.

Relationships between prothrombin time and thrombin generation

Discussion

Prior to PCC administration, there was a significant negative correlation between INR with thrombin peak

To our knowledge, this is the first case-series that used a sequence of traditional and global coagulation tests to

Table 2

Individual clinical and laboratory results of patients who received prothrombin complex concentrate for warfarin reversal

Patient Age (years) Type of bleed Received FFP Clinical outcome Aspirin use PCC dose (IU/kg) INR Baseline 30 min 24 h Thrombin peak (nmol) Baseline 30 min 24 h ETP (nmolMmin) Baseline 30 min 24 h R-time (min) Baseline 30 min 24 h

1

2

3

4

5

6

7

8

85 SDH No Lived No 22

69 ICH Yes Lived No 20

69 ICH/SAH/IVH Yes Died No 23

84 SDH/ICH No Lived No 24

39 SDH/ICH No Died Yes 31

85 ICH No Died Yes 18

63 SDH No Lived No 22

83 SDH Yes Died No 30

1.42 1.19 1.1

3.50 2.04 1.08

4.59 1.84 1.57

1.87 1.5 1.31

5.04 2.77 –

2.93 1.90 1.57

2.29 1.49 1.31

2.51 1.69 1.34

269 389 98

90 234 342

22 258 341

207 348 284

39 308 –

125 316 338

156 343 292

75 215 278

2386 2964 1530

612 1374 2057

148 1149 1444

1159 1953 1534

226 1908 –

976 2266 2245

1127 2784 1895

486 1142 1083

5.5 7.2 13.9

8.0 3.7 4.3

15.4 10.4 8.4

7.3 3.2 5.2

21.2 6.4 –

7.2 4 6.9

8.4 1.8 6.2

9.6 4.2 7.2

The 2-h time point is not reported in the table because of missing data points due to surgical procedures, lack of venous access and radiology scans. FFP, fresh frozen plasma; ICH, intracerebral hemorrhage; IVH, intraventricular hemorrhage; PCC, prothrombin complex concentrate; SAH, subarachnoid hemorrhage; SDH, subdural hematoma.


446 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 4

Fig. 1

(a)

(b)

4.0

150.0

3.5 *P < 0.01 vs. baseline

*P < 0.05 vs. baseline

3.0 10.0 *

2.0

* *

1.5

R (min)

INR

2.5

* 5.0

1.0 0.5 0.0 0

0.5

2

0.0

24

0

Time point (h) (c) 400

*

2000

300 250 200 150 *P < 0.01 vs. baseline

ETP (nmol/l) * min

Thrombin (nmol/l)

24

*

*

100

2

Time point (h)

(d) 2500

350

0.5

**

1500

1000 *P < 0.01 vs. baseline **P < 0.05 vs. baseline

500 50 0

0 0

0.5

2

24

Time point (h)

0

0.5

2

24

Time point (h)

Changes in coagulation parameters over time.

assess warfarin reversal in patients with intracranial bleeding. We have shown that administration of a three-factor PCC corrects the INR, ETP, thrombin peak and R-time. Further, a significant association between thrombin generation parameters with INR and TEG was observed prior to administration of PCC. However, INR and TEG values did not correlate with most thrombin generation parameters after PCC administration. The loss of a relationship between INR and thrombin generation after PCC administration may be explained in part by the sensitivity of the PT/INR to circulating clotting factors, particularly factor VII, which is included in the three-factor PCC formulation in this study. This is a clinically important finding because INR is routinely used to assess the adequacy of anticoagulation reversal, yet does not appear to be associated with thrombin generation in this setting. If one can deduce that increased thrombin generation is associated with cessation of bleeding, then INR correction may lead clinicians to incorrectly assume that the patient is no longer at risk for bleeding diatheses. Ultimately, the best laboratory test to assess adequate reversal of anticoagulation is one that exhibits a strong relationship with clinical outcome.

Some authors have suggested that thrombin generation parameters are superior to INR in determining anticoagulation reversal after administration of hemostatic agents [7,9]. This premise is consistent with a recent phase IIIb study that compared a four-factor PCC to FFP for reversal of anticoagulation with warfarin in patients with a variety of major bleeding events [12]. Although rapid INR correction was achieved in 62% of patients in the PCC group versus only 10% in the FFP group, no difference was observed between groups in ‘effective hemostasis’. Additionally, in patients with warfarinassociated intracranial hemorrhage, others reported high mortality rates and hematoma expansion despite rapid INR correction with a four-factor PCC in 80% of patients [13]. In this study, it was unexpected that the INR did not fully correct in most of the patients despite PCC and vitamin K therapy. It is possible that these patients were underdosed with PCC. TEG values generally corrected 30 min after PCC administration and remained in the normal range across the 24 h interval. Surprisingly, patient 1’s R value increased throughout the 24 h interval despite a


Global tests for warfarin reversal following prothrombin complex concentrate Voils et al. 447

declining INR. This was an unexpected finding given an approximate half-life of factor II of 60 h. In contrast, thrombin generation parameters (with the exception of lag time) corrected 30 min after PCC administration and this effect persisted through 24 h. Although these data support the notion that TEG and TGA may be clinically useful to assess sustained reversal of warfarin, it appears the INR is equally as informative as prolonged INR was associated with poor clinical outcome. Interestingly, CI was elevated in three of eight patients 30 min after administration of PCC, suggesting these patients experienced an ‘overshoot’ hypercoagulability immediately after PCC administration and may be at risk for thromboembolic events. Although assessment of safety events was not the goal of the current study, we have previously reported a thromboembolic rate of 9% in 45 patients who received a three-factor PCC for warfarin reversal [14], a rate that is substantially higher than reported in a meta-analysis of thromboembolic events in patients receiving PCC for warfarin-associated bleeding or urgent surgery [15]. However, the incidence of thromboembolic events following PCC administration for warfarin reversal is unknown and may be associated with underlying disease state, type of PCC (three-factor versus four-factor) and dose [7]. In surgical patients, R-time and MA have been associated with development of in-hospital venous thromboembolism events, but it remains to be seen which, if any, global coagulation test can predict thromboembolic events following anticoagulation reversal [16–18]. A major strength of our study is the in-vivo assessment of the effect of anticoagulation reversal on global coagulation tests, whereas previous studies utilized in-vitro or ex-vivo designs [7,9]. The limitations include a relatively small sample size and inability to quantify hematoma expansion because we included a heterogeneous group of patients with intracranial bleeding. Although we reported hospital mortality, there were not enough patients to perform multivariate modeling to assess the effect of important potential confounders such as age on the relationship between post-PCC laboratory values and outcome. Finally, three patients with INR values more than 1.5 thirty minutes after PCC also received FFP as ‘salvage’ therapy, making it unclear if the effect of PCC alone was persistent at the 2 and 24 h time points in this study.

correlated well with thrombin generation before administration of PCC, but this relationship was lost afterward.

Acknowledgements The authors thank Maureane Hoffman, MD, PhD, for her assistance with the manuscript. Conflicts of interest

There are no conflicts of interest.

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Following PCC administration, TGA and TEG parameters tended to normalize over the 24 h observational period. Conversely, the INR did not fully correct despite the addition of vitamin K. Patients that died tended to be older and had the most prolonged INR values across the study period. INR and TEG values

17

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