Thrombin Formation for Children on Lovenox Steven Ignell, BA
Definitions Anticoagulation Historically this refers to inhibiting thrombin formation Measured by PTT, INR, anti-xa Hypo and hypercoagulation Relates to overall hemostatic capacity Reflect increased risk of bleeding or risk of thrombosis Can be measured with global functional measures of hemostasis such as TEG/ROTEM
The Hemostatic Process: Interaction between Platelets Coagulation factors Fibrinolytic pathway Vascular endothelium Subendothelium Inflammatory cells and mediators
Anti-coagulation Goals Hypercoaglable Normocoagulable Hypocoagulable
Anticoagulation Goals Anticoagulation hypocoagulable Goal of anticoagulation is to prevent thrombosis by reducing thrombin formation What is optimal method to monitor therapeutics that reduce thrombin formation?
Measures of Hemostasis Anti-Xa levels reflect the degree of enoxaparin inhibition on Xa (direct measure of drug effect) Does not reflect actual amount of thrombin formation Inhibition of Xa is not analyzed in relation to: Baseline thrombin formation or platelet function Does not reflect global hemostatic capacity Car speed analogy
Measures of Hemostasis Current guidelines for anti-xa deep vein thrombosis treatment levels are 0.5 units/ml May over or under treat based upon baseline thrombin formation or platelet function
Measures of Hemostasis Thromboelastography (TEG) provides a global functional analysis of each hemostasis phase
TEG-directed Anticoagulation Unknown what goals should be No trials performed to determine Indication for use of anticoagulation Therapeutic goals for anticoagulation Makes implementation difficult. For the record no such trials for anti-xa approach either. Anti-Xa goal range, extrapolated from heparin values and PTT data in adults.
Direct Measures of Thrombin Formation Thrombin-antithrombin complexes Prothrombin Fragments 1&2 Thrombin generation assay Thrombinoscope
Study Objectives To determine if there is a correlation between anti- Xa and TEG parameters for children on enoxaparin. Hypothesize that there will be discordance between anti-xa and TEG values
Study Objectives To determine if anti-xa or TEG parameters correlate with measures of thrombin formation (PF1&2, TAT, TG). Hypothesize that TEG-R values correlate with measures of thrombin formation better than anti-xa values.
Study Objectives This preliminary data will support funding for multicenter trials to determine what values are associated with adverse events to then set up therapeutic trials of anti-xa vs TEG directed anticoagulation
Methods For children on enoxaparin in the PICU/CICU TEG and Anti-Xa labs were drawn simultaneously at at time when anti-xa was being drawn clinically Extra plasma can be held for PF1&2, TAT and thrombin generation testing. Exclusion Criteria Weight 3kg Unable to perform TEG testing due to device availability
Discordance between hemostatic parameters TEG R-Time<5 minutes and Anti-Xa 0.5 units/ml Direct discordance between measures of thrombin formation TEG G-Value>11 dynes/s 2 and Anti-Xa 0.5 units/ml Measure of reduced thrombin but still increased platelet function Still at risk of thrombotic event theoretically
Results 28 children were enrolled with evaluable data 23 children also had Heparinase TEG values
Table 1: Patient Population Table 1a N Lovenox Age (years) 28 3.25 (0.43,15.05) Weight (kg) 28 13.35 (5.1,56.93) Weight for age (%) 28 28.5 (4.48,64.65) Male 28 46.4% (13) Hispanic 28 3.6% (1) Race 28 71.4% White (20), 17.9% Black (5), 10.7% Asian (3) Results presented as Median (IQR), Mean±Standard Devia8on (N), or Percent (N)
Table 1 Table 1b N Lovenox Chronic Cardiac disease 28 50.0% (14) Chronic Heme/Onc Disease 28 21.4% (6) Chronic Neuro Disease 28 17.9% (5) Chronic Pulmonary Disease 28 39.3% (11) Chronic Other Disease 28 21.4% (6) Lovenox for Prophylaxis 28 50.0% (14) Surgery in Past 12 Weeks 28 53.6% (15) Results presented as Median (IQR), Mean±Standard Devia8on (N), or Percent (N)
Table 1 Table 1c N Lovenox PELOD at Admission 28 11 (10,12) PELOD Day of Blood Draw 14 10 (1,11) PIM- 2 at Admission 28-3.62 (- 4.37,- 2.91) PRISM at Admission 28 7 (3,9) Results presented as Median (IQR), Mean±Standard Devia8on (N), or Percent (N)
Table 1 Table 1d N Lovenox WBC (k/cumm) 28 10.67±4.38 Hgb (g/dl) 21 10.03±2.00 Hct (%) 21 31.09±6.46 Plt (k/cumm) 21 238 (158.5,315.5) RDW (%) 28 15.58±1.82 AnZ- Xa (units/ml) 26 0.63±0.27 Enoxaparin Dose (mg/kg) 28 1.05±0.46 Time on Current Enoxaparin Dose at Blood Draw (Hrs) 28 22.5 (16,107.25) Results presented as Median (IQR), Mean±Standard Devia8on (N), or Percent (N)
Outcomes Outcomes N Lovenox In- hospital Mortality 28 21.4% (6/28) ICU Days 28 21.5 (15,36.75) Intubated Vent Days 28 13 (5,28) Results presented as Median (IQR), Mean±Standard Devia8on (N), or Percent (N)
Results 35.7% (10/28) of children had discordant results 5 children were discordant based on R-time 8 children were discordant based on G-value 3 children discordant with both R-time and G-value
Scatter of R-Time 1.20 B 1.00 B 0.80 Anti-Xa (units/ml) 0.60 0.40 T B B B B Discordance T=Thrombotic Event B=Bleeding Event 0.20 0.00 0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 Kaolin TEG R-Time (s)
Scatter of TEG G-Value 1.20 B 1.00 B 0.80 Anti-Xa (Units/mL) 0.60 0.40 B B B B T Discordance T=Thrombotic Event B=Bleeding Event 0.20 0.00 0.0 5.0 10.0 15.0 20.0 25.0 Kaolin TEG G-Value (Dynes/s^2)
R-Time Regression R 2 Linear=0.135
Results Table 2a Concordant N=18 Discordant N=10 p value Age (years) 0.95 (0.35,13.9) 11.65 (0.55,15.88) 0.226 Weight (kg) 9.25 (4.43,53.28) 37.95 (5.93,57.25) 0.382 Weight for age (%) 12.7 (3.68,95.8) 46.95 (8.73,61.68) 0.832 Male 44.4% (8) 50.0% (5) 1 Hispanic 5.6% (1) 0.0% (0) 1 Race 72.2% White, 22.2% Black, 5.6% Asian 70.0% White, 10.0% Black, 20.0% Asian Results presented as Median (IQR), Mean±Standard Devia8on (N), or Percent (N) 0.408
Results Table 2b Concordant N=18 Discordant N=10 p value Chronic Caridac disease 55.6% (10) 40.0% (4) 0.695 Chronic Heme/Onc Disease 22.2% (4) 20.0% (2) 1 Chronic Neuro Disease 27.8% (5) 0.0% (0) 0.128 Chronic Pulmonary Disease 50.0% (9) 20% (2) 0.226 Chronic Other Disease 16.7% (3) 30% (3) 0.634 ProphylacZc IndicaZon for AnZcoags 61.1% (11) 30% (3) 0.236 Past Surgical History in 12 Weeks 44.4% (8) 70.0% (7) 0.254
Results Table 2c Concordant N=18 Discordant N=10 p value WBC (k/cumm) 9.25 (5.57,12) 11.55 (9.35,14.03) 0.089 Hgb (g/dl) 9.79±2.06 (14) 10.53±1.93 (7) 0.437 Hct (%) 30.67±6.63 (14) 31.91±6.52 (7) 0.688 Plt (k/cumm) 229 (130.5,293.5) 301 (199,395) 0.172 RDW (%) 16.31±1.61 (18) 14.26±1.43 (10) 0.002 Results presented as Median (IQR), Mean±Standard Devia8on (N), or Percent (N)
Results Table 2d PELOD at Admission PELOD Study Day Started PIM- 2 at Admission PRISM at Admission Concordant N=18 Discordant N=10 p value 11 (10,12) 10.5 (1,12) 0.588 10.5 (1,11) 5.5 (0.25,10.75) 0.454-3.73 (- 4.36,- 3.01) - 3.45 (- 4.63,- 2.44) 0.524 4.5 (2.75,8.25) 7.5 (6,12.25) 0.175 Results presented as Median (IQR), Mean±Standard Devia8on (N), or Percent (N)
Results presented as Median (IQR), Mean±Standard Devia8on (N), or Percent (N) Results Table 2e Concordant N=18 Discordant N=10 p value AnZ- Xa 0.56±0.29 (16) 0.72±0.2 (10) 0.145 Enoxaparin Dose (mg/kg) 1.02±0.54 (18) 1.1±0.26 (10) 0.633 Time at current anzcoag dose (hrs) 28 (16,137.5) 16.25 (15.63,93.75) 0.464 Heparin_Effect 1.3 (0.2,4.85) 0.3 (0.1,0.5) 0.193 Kaolin TEG G- value 6.9 (4.68,9.97) 13.15 (11.38,19.48) 0.001 Kaolin TEG MA 58.7 (50.7,66.85) 72.45 (69.45,79.55) 0.003 Kaolin TEG R- Time 7.65 (5.78,14.45) 4.95 (4.5,6.08) 0.003 Kaolin TEG Angle 63.3 (51.25,69.85) 72.4 (70.25,75.5) 0.009 Kaolin TEG Delta R 0.65 (0.5,1.4) 0.5 (0.4,0.65) 0.077 Kaolin TEG K 1.95 (1.28,3.2) 1.2 (1,1.38) 0.01 Kaolin TEG Ly%30 0.05 (0,0.4) 0 (0,1.2) 1
Outcomes Concordant N=18 Discordant N=10 p value In- hospital Mortality 27.8% (5) 10% (1) 0.375 ICU Days 21.5 (17.25,42.5) 23.5 (10.5,45) 0.494 Intubated Vent 17 (8.5,33) 6.5 (0.75,21.5) 0.083 Days Results presented as Median (IQR), Mean±Standard Devia8on (N), or Percent (N)
Correlations Pearson r P value RDW vs AnZ- Xa - 0.354 0.076 RDW vs Kaolin TEG R- Time 0.357 0.062 RDW vs Kaolin TEG G- Value - 0.486 0.009
Limitations Small Sample Sizes Enrolling more patients to increase the sample size NEED ADDITIONAL CENTERS We can provide TEG reagents and send us plasma for thrombin measure testing. Just need you to draw blood at same time as anti-xa values and run a TEG
Conclusions There is a high rate of discordance between TEG parameters and anti-xa levels, indicating some patients remain hypercoagulable (increased thrombin generation and increased platelet function) despite anti-xa values.5 units/ml
Conclusions Cont d Decreased RDW is associated with increased measures of thrombin generation and platelet function Unknown significance or pathophysiology Larger multicenter studies are needed to assess if TEG directed Lovenox administration is more effective than an anti-xa guided approach
Questions?
Delta R Regression R 2 Linear=0.112
Complications 6 Children had bleeding events after the start of Lovenox 1 patient had a thrombotic event after the start of Lovenox No Complica8ons N= 21 Bleeding N=6 No Complica8ons vs Bleeding AnZ- Xa 0.62±.27 (19) 0.68±.29 (6) 0.689 Kaolin TEG R- Time Kaolin TEG G- value Kaolin TEG Delta R In- Hospital Mortality ICU Days 6.9 (5,9.85) 8.3 (6.55,12.55) 6.45 (5.5.3,24.08) 11.95 (3.6,17.88) 0.629 0.476 0.5 (.5,1) 0.7 (.45,2.9) 0.575 14.3% (3) 50.0% (3) 0.101 21 (16,35) 35.5 (14.75,124.25) 0.345 Vent Days 13 (2.5,20.5) 28 (8.25,104.5) 0.139 Results presented as Median (IQR), Mean±Standard Devia8on (N), or Percent (N)