Apheresis Anticoagulant Removal Oluwatoyosi Onwuemene, MD MS May 6th, 2017
Talk Outline Case presentation Factors associated with drug removal TPE s effects on hematologic parameters Anticoagulant properties Studies of anticoagulant removal TPE s effects on warfarin TPE s effects on heparin TPE-associated bleeding risk Summary and conclusions
Case Presentation
Case Presentation History of Present Illness 44 y.o female with tumefactive MS Admitted with encephalopathy Plasma exchange requested Past Medical History H/o FVL and recurrent strokes Plasma cell dyscrasia Pertinent Meds Rivaroxaban, 20 mg PO once daily
TPE Course Date TPE # Hgb Hct Plt FGN aptt PT PRBC 10/08 9.6 29 133 36.8 10/09 1 10.5 32 139 330 83.4 13.5 10/10 2 10.8 31 128 167 49.5 16.1 10/11 10.1 30 112 66.2 10/12 8.9 26 136 34.2 10/13 3 7.5 22 154 379 110.7 12.3 10/14 7.1/11.1 20 173 99.8 2U 10/15 4 10.7 30 72 64.4 10/16 9.6 28 96 10/17 5 8.6 25 162 10/18 8.7 26 257 126 24.5 10.5 10/19 8.2/7.1 25/22 10/20 6 7.7 23 361 227
Hemoglobin Trends Heparin stopped 1 2 3 2U PRBC 4 5 6
CT Showed RP Bleed CT abdomen and pelvis Right psoas hematoma Right rectus abdominus hematoma
Clinical Question Did TPE contribute to bleeding risk?
Factors Associated with TPE Drug Removal
TPE Characteristics Plasma Volume Exchanged Plasma solutes removed (%) 1.0 63 1.5 78 2.0 86 Shelat. Am J Med 123:777-784, 2010
TPE-mediated Drug Effects Direct removal of circulating drug Drug action prolongation
TPE Drug Removal Drug Characteristics Volume of Distribution (V D ) Pharmacotherapy 27:1529-1549, 2007 Plasma Ther Transfus Technol 5:305-317, 1984
Protein Binding Protein Binding TPE Drug Removal Pharmacotherapy 27:1529-1549, 2007 Plasma Ther Transfus Technol 5:305-317, 1984
Drug Removal Determinants Drug-dependent Time from dose to TPE initiation Protein binding Volume of distribution Blood levels vs. biologic effect TPE-dependent Duration of TPE Successive TPE sessions Plasma volume removed Seminars in Dialysis 2:176-189, 2012
TPE hematologic effects
TPE Hematologic Effects Lab Parameter Pre Post 24 Hrs Hgb (g/dl) 13.1 (6 16.5) Platelets (x 10 9 /L) 296 (146 595) Prothrombin Index (% of normal) 88 (76 100) PTT (s) 36 (30 - > 120) Fibrinogen (g/l) 3.6 (0.9 5.75) ATIII 130 (91 146) Factor VIII 144 (102 255) 11.5 (4.9 17.8) 264 (131-482) 35 (10 92) 59 (39 - > 120) 0.86 (0.2 3.52) 39 (27 45) 25 (14 95) 12.5 (5.5 16.0) 278 (187 483) 80 (69 96) 38 (55-32) 2.17 (0.7 4.0) 107 (68 160) 89 (31 161) Wood and Jacobs. J Clin Apher 3:l24-128 (1986)
TPE Effects on Clotting Assays Flaum et al. Blood 1979 54:694-702
TPE Effects on Clotting Factors Flaum et al. Blood 1979 54:694-702
All Factors Decreased
TPE Effects on Fibrinogen Flaum et al. Blood 1979 54:694-702
TPE Effect on Fibrinogen Zantek et al. J Clini Apher 29:75 82 (2014)
TPE Effect on Factor II Zantek et al. J Clin Apher 29:75 82 (2014)
TPE-Relevant Anticoagulant Properties
Warfarin AC R Mode of Action V d (L) Protein Binding (%) t 1/2α (h) Warfarin PO Blocks vitamin K oxide reductase to decrease factors II, VII, IX, X, C & S 10 99 35 Holford. Clin Pharmacokinet. 1986. Nov-Dec;11(6):483-504.
Heparin AC R Mode of Action V d (L) Protein Binding (%) t 1/2α (h) Heparin IV SC Binds AT, HCII, & IXa to inactivate IIa, Xa, IXa, & XIIa 3.5-7 high 1.5 LMWH SC Inactivates Xa &, to a lesser extent, IIa 3 80 4.5 Hirsh & Raschke. Chest 2004; 126:188S 203S
Xa Inhibitors AC R Mode of Action V d (L) Protein Binding (%) t 1/2α (h) Fondaparinux SC Binds AT, inactivates Xa 7-11 94 17-21 Apixaban PO Inhibits free and clot-bound Xa 21 87 12 Edoxaban PO Inhibits free Xa & IIase activity & IIainduced platelet aggregation 107 55 10-14 Rivaroxaban PO Inhibits free, IIase-associated & clotassociated Xa 50 92-95 5-13 J Clin Pharmacol. 2014 Aug;54(8):917-27 Eur J Clin Pharmacol. 2014 Nov;70(11):1339-51 Br J Clin Pharmacol. 2013 Feb;75(2):476-87 Clin Pharmacokinet. 2002;41 Suppl 2:1-9
Direct Thrombin Inhibitors AC R Mode of Action V d (L) Protein binding (%) t 1/2α (h) Bivalirudin IV Inhibits free & clot-bound IIa & IIamediated platelet activation/aggregation 14 ~0 0.4 Argatroban IV Direct thrombin inhibitor 12.18 54 0.7-0.9 Dabigatran PO Competitive direct IIa inhibitor 60-70 34-35 12-17 J Clin Pharmacol. 2011 Jun;51(6):805-18 J Thromb Haemost. 2011 Nov;9(11):2168-75 Expert Rev Cardiovasc Ther. 2010 Dec;8(12):1673-81
Anticoagulant properties AC R Mode of Action V d (L) Heparin Bivalirudin IV SC IV 1) Binds AT, HCII, & IXa to inactivate IIa, Xa, IXa, & XIIa Inhibits free & clot-bound IIa & IIamediated platelet activation/aggregation Protein Binding (%) t 1/2α (h) 3.5-7 high 1.5 14 ~0 0.4 Argatroban IV Direct thrombin inhibitor 12.18 54 0.7-0.9 LMWH SC Inactivates Xa &, to a lesser extent, IIa 3 80 4.5 Fondaparinux SC Binds AT, inactivates Xa 7-11 94 17-21 Warfarin PO Blocks vitamin K oxide reductase to decrease factors II, VII, IX, X, C & S 10 99 35 Apixaban PO Inhibits free and clot-bound Xa 21 87 12 Dabigatran PO Competitive direct IIa inhibitor 60-70 34-35 12-17 Edoxaban Rivaroxaban PO PO Inhibits free Xa & IIase activity & IIainduced platelet aggregation Inhibits free, IIase-associated & clotassociated Xa 107 55 10-14 50 92-95 5-13
Anticoagulant Removal Studies
Anticoagulant Removal studies Author/Year (N) AC Indication Procedure TPE effect Bleeding or Thrombosis Rahawi 2017 (1) Enoxaparin PE atpe t 1/2 from 7 to 1.6h CVC oozing Hematuria* Lam 2017 (1) Apixaban Afib ptpe Anti Xa 0.84-0.35 Hemorrhagic pericardial effusion Zantek 2013 (8) Warfarin - atpe INR 2.09-4.12 CVC oozing (n=1) Fistula thrombosis Kaplan 2016 (6) Heparin - ptpe atpe aptt Anti Xa NR
TPE Effects on Warfarin
TPE Effects on INR Zantek et al. J Clin Apher 29:75 82 (2014)
Zantek et al. J Clin Apher 29:75 82 (2014)
TPE Effects on INR Zantek et al. J Clin Apher 29:75 82 (2014)
TPE Effects on Heparin
With Albumin Replacement Kaplan et al. J Clin Apher 31:507 515 (2016)
With Plasma Replacement Unchanged infusion rate Infusion rate 25% Infusion stopped Infusion rate 65% Kaplan et al. J Clin Apher 31:507 515 (2016)
Post-aTPE Anti Xa and aptt TPE# Infusion Anti Xa aptt (s) AT(%) Pre Post Pre Post Pre Post 1 -- 0.16 0.10 29 41 92 34 2 0.31 0.12 45 127 83 26 3 0.29 0.36 41 >240 95 35 4 0.18 0.19 37 139 95 34 5 0.18 0.20-158 - 28 Kaplan et al. J Clin Apher 31:507 515 (2016)
The anti Xa Assay Typically chromogenic Known amounts AT & Xa added Inhibitory complex inactivates Xa Excess Xa measured heparin levels = intensity Use endogenous/add exogenous AT Results confounded Factor deficiency AC removal ates and Weitz. Circulation. 2005;112:e53- Newall. Methods Mol Biol. 2013;992:265-72
TPE and Bleeding Risk
Studies of TPE Bleeding Risk Author Year Sutton 1989 N 627 (5235) Albumin only replacement Bleeding Precautions 69%* NR Bleeding Complications Bleeding (<1%) Brain hemorrhage (1), groin hematoma (1) Couriel 1994 63 (381) NR NR Hemothorax (1.6%) Brain hemorrhage (1.6%) Yeo 2005 54 (568) 50% NR Mild bleeding (13%) Major bleeding (1%) Shemin 2007 174 (1727) 57% Plasma for bleeding risk Exit site bleeding (1.2%) Cid 2014 317 (2730) 73% Plasma for bleeding risk GI hemorrhage (1.5%) Samanci 2014 110 (734) 11.8% NR Catheter-related hematoma (1%)
Summary and Conclusions
Summary and Conclusions TPE affects anticoagulation Removal of anticoagulant drugs Removal of procoagulant proteins Removal of coagulant proteins Contribution to bleeding risk unclear Other factors should be considered Available data is limited More prospective studies needed