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
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
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
Drug Characteristics TP
E D
rug
Rem
ova
l
Volume of Distribution (VD)
Pharmacotherapy 27:1529-1549, 2007
Plasma Ther Transfus Technol 5:305-317, 1984
Protein Binding TP
E Dru
g Rem
oval
Protein Binding
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
Lab Parameter Pre Post 24 Hrs
Hgb (g/dL) 13.1 (6 – 16.5)
11.5 (4.9 – 17.8)
12.5 (5.5 – 16.0)
Platelets (x 109/L) 296 (146 – 595)
264 (131-482)
278 (187 – 483)
Prothrombin Index (% of normal)
88 (76 – 100)
35 (10 – 92)
80 (69 – 96)
PTT (s) 36 (30 - > 120)
59 (39 - > 120)
38 (55-32)
Fibrinogen (g/L) 3.6 (0.9 – 5.75)
0.86 (0.2 – 3.52)
2.17 (0.7 – 4.0)
ATIII 130 (91 – 146)
39 (27 – 45)
107 (68 – 160)
Factor VIII 144 (102 – 255)
25 (14 – 95)
89 (31 – 161)
Wood and Jacobs. J Clin Apher 3:l24-128 (1986)
Warfarin
AC R Mode of Action Vd
(L) Protein
Binding (%) t1/2α
(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 Vd
(L) Protein
Binding (%) t1/2α
(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 Vd
(L) Protein
Binding (%) t1/2α
(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 & IIa-
induced platelet aggregation 107 55 10-14
Rivaroxaban PO Inhibits free, IIase-associated & clot-
associated Xa 50 92-95 5-13
Clin Pharmacokinet. 2002;41 Suppl 2:1-9
Br J Clin Pharmacol. 2013 Feb;75(2):476-87
Eur J Clin Pharmacol. 2014 Nov;70(11):1339-51
J Clin Pharmacol. 2014 Aug;54(8):917-27
Direct Thrombin Inhibitors
AC R Mode of Action Vd
(L) Protein
binding (%) t1/2α
(h)
Bivalirudin IV Inhibits free & clot-bound IIa & IIa-
mediated 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
Expert Rev Cardiovasc Ther. 2010 Dec;8(12):1673-81 J Clin Pharmacol. 2011 Jun;51(6):805-18
J Thromb Haemost. 2011 Nov;9(11):2168-75
Anticoagulant properties
AC R Mode of Action Vd (L) Protein
Binding (%) t1/2α
(h)
Heparin IV SC
1) Binds AT, HCII, & IXa to inactivate IIa, Xa, IXa, & XIIa
3.5-7 ⇡⇡ high 1.5
Bivalirudin IV Inhibits free & clot-bound IIa & IIa-
mediated platelet activation/aggregation 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 PO Inhibits free Xa & IIase activity & IIa-
induced platelet aggregation 107 55 10-14
Rivaroxaban PO Inhibits free, IIase-associated & clot-
associated Xa 50 92-95 5-13
Anticoagulant Removal studies
Author/Year (N)
AC Indication Procedure TPE effect Bleeding or Thrombosis
Rahawi 2017 (1)
Enoxaparin PE aTPE ↓ t1/2 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
With Plasma Replacement
Kaplan et al. J Clin Apher 31:507–515 (2016)
Unchanged infusion rate Infusion rate ↓ 25%
Infusion stopped Infusion rate ↑ 65%
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
Newall. Methods Mol Biol. 2013;992:265-72 Bates and Weitz. Circulation. 2005;112:e53-
e60
Studies of TPE Bleeding Risk
Author Year
N Albumin only replacement
Bleeding Precautions
Bleeding Complications
Sutton 1989
627 (5235)
69%* NR 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%)