Apheresis Anticoagulant Removal Oluwatoyosi Onwuemene, MD MS May 6th, 2017
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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
Heparin stopped
Hemoglobin Trends
1 2 3 4 5 6 2U PRBC
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
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
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)
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 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
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
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)
Zantek et al. J Clin Apher 29:75–82 (2014)
TPE Effects on INR
TPE Effects on Heparin
With Albumin Replacement
Kaplan et al. J Clin Apher 31:507–515 (2016)
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
TPE and Bleeding Risk
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%)
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
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