Neuraxial anesthesia in obstetric patients receiving anticoagulant and antithrombotic drugs

International Journal of Obstetric Anesthesia (2010) 19, 193–201 0959-289X/$ - see front matter c 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ijoa.2009.06.008



REVIEW ARTICLE

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Neuraxial anesthesia in obstetric patients receiving anticoagulant and antithrombotic drugs A.J. Butwick, B. Carvalho Department of Anesthesiology, Stanford University School of Medicine, Stanford, California, USA Introduction Spinal hematoma and neuraxial anesthesia Guidelines for neuraxial techniques and anticoagulation Individual drugs Heparin Low-molecular-weight heparins Warfarin Aspirin Fondaparinux Thienopyridines (clopidogrel, ticlopidine) Glycoprotein IIb/IIIa inhibitors Direct thrombin inhibitors References

Introduction Anticoagulation is indicated for a variety of obstetric and medical conditions in women of childbearing age. Recent guidelines from national and international organizations, the Pregnancy and Thrombosis Working Group and the American College of Chest Physicians, have highlighted the importance of anticoagulant therapy in the prophylaxis and treatment of venous thromboembolism in pregnancy, and in pregnant patients with mechanical heart valves.1,2 Thromboprophylaxis may also be prescribed for the prevention of adverse pregnancy outcomes such as recurrent early pregnancy loss and placental abruption, and in patients with inherited or acquired thrombophilias.

Spinal hematoma and neuraxial anesthesia Epidural spinal hematomas are the most common type of spinal hematoma, followed by subarachnoid hematomas (75% and 16% of published cases reported between 1826 and 1996 respectively), with many cases having Accepted June 2009 Correspondence to: Dr. Alexander Butwick, Department of Anesthesiology (MC:5640), Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305 USA. Fax: 650-725-8544. E-mail address: [email protected]

unknown etiology.3 Anticoagulant and antithrombotic drugs can increase the risk of spinal hematoma formation, especially following neuraxial blockade.4 In particular, the introduction of low-molecular-weight heparin (LMWH) in the United States in 1993 was associated with an increased incidence of patients with spinal hematoma following neuraxial anesthesia (nearly 60 cases were reported over a 5-year period).5 Neuraxial anesthetic practice guidelines have been developed and revised to minimize the risk of spinal hematoma in patients receiving LMWH as well as other newer anticoagulants.6,7 The use of anticoagulant and antithrombotic drugs in pregnant patients poses significant challenges to obstetric anesthesiologists as neuraxial techniques are commonly used to provide labor analgesia and anesthesia for cesarean delivery. The incidence of spinal hematoma after neuraxial blockade in obstetric patients receiving anticoagulation remains unknown. A retrospective study by Moen et al. of neuraxial anesthetics, which included 50 000 spinal and 205 000 epidural blocks in obstetrics, reported one spinal hematoma following obstetric epidural catheter removal and one following spinal blockade, both in patients with HELLP syndrome.8 Other studies (meta-analysis/national audit) of complications following epidural blocks in obstetric patients reported an incidence between 0 and 0.5:100 000.9,10

194

Neuraxial anesthesia with anticoagulant drugs

The aim of this review is to provide obstetric anesthesiologists with a summary of current guidelines from different international anesthetic societies for neuraxial anesthetic practice in patients receiving anticoagulant and antithrombotic drugs. Anticoagulant drugs currently used in clinical obstetric practice and their relevant pharmacokinetic (PK) and pharmacodynamic (PD) properties will be discussed. PK parameters in this review included maximal concentration (Cmax), lag-time in hours (Tmax) to achieve Cmax, area under the curve (AUC) which is proportional to the administered dose and the clearance, and elimination half-life (t1/2).

Guidelines for neuraxial techniques and anticoagulation A number of countries have published guidelines for the safe timing and administration of neuraxial blockade in patients receiving antithrombotic agents. The guidelines from various national anesthetic societies [American ¨ steriche Gesellschaft Society of Regional Anesthesia,5 O fu¨r Ana¨sthesiologie und Intensivmedizin (Austria),11 Belgian Association for Regional Anesthesia,12 Socie´te´ franc¸aise d’anesthe´sie et de re´animation (France),13 Deutsche Gesellchaft fu¨r Ana¨sthesiologie und Intensivmedizin (Germany),14 Nederlandse Vereniging voor Anesthesiologie (Netherlands),15 Sociedad Espanola de Anaestesiologta y Keanimacidn (Spain)16] are summa-

rized in Tables 1–3. The guidelines are limited by a lack of robust data assessing specific risk, and rely upon consensus expert opinion following review of case reports and relevant PK-PD data. Previous reviews have questioned whether these guidelines can be described as ‘standard of care’, and have expressed concern regarding the medico-legal implications of such guidelines on clinical practice.17,18 Nonetheless, practicing anesthesiologists are likely to adhere to national guidelines on neuraxial anesthetic practice in patients receiving prophylactic or therapeutic anticoagulant drugs in the preoperative and postoperative periods. There are no specific recommendations for neuraxial anesthetic practice in obstetric patients receiving anticoagulation. The physiological changes associated with pregnancy are likely to affect the PK-PD of many anticoagulants and antithrombotic agents. The unpredictable timing of labor and delivery can also alter anesthetic planning and decision-making for anticoagulated patients. Contingency plans for labor analgesia and cesarean delivery anesthesia should be made in all obstetric patients receiving anticoagulation.

Individual drugs The following anticoagulant and antithrombotic drugs will be reviewed: heparin, low molecular weight heparins, warfarin, aspirin, fondaparinux, thienopyridines (clopi-

Table 1 Guidelines from national anesthetic societies for the timing of neuraxial anesthesia in patients receiving unfractionated heparin, low-molecular-weight heparins and warfarin Austria11

Belgium12

Unfractionated heparin s.c. 4h —a before*  after*,  1h 1h i.v. before* 4h —a * after 1h 1h Low-molecular-weight heparin Prophylactic before* 12 h 12 h after* 4h 4h Therapeutic before* after* Warfarin before* after*

France13

Germany14

Netherlands15

Spain16

12 h 6-8 h

4h 1h

No CI —

No CI —

4h 6-8 h

4h 1h

4-6 h 1h

4h 1h

— (NB)/2-4 h (CW) 1h

10-12 h 4-12 h

12 h 2-4 h

10 h 2h

12 h 6h

10-12 hd 6-8 h [first dose] (NB)e/>2h (CW)

b

United States5

No time intervalc 1h

24 h 4h

24 h 4h

24 h 24 h

24 h 2-4 h

24 h 24 h

24 h 6h

24 h 24 h (NB)/2 h (CW)e

INR <1.4 Restart after CW

INR <1.4 Restart after CW

INR <1.5 —

INR <1.4 Restart after CW

INR <1.8 —

INR 61.5 Restart after CW

— (NB)f /INR<1.5 (CW) Restart after CW

NB=Neuraxial block; CW=Catheter withdrawal; APTT=activated partial thromboplastin time; INR=international normalized ratio. CI = contraindication. * Timing interval before or after neuraxial block / catheter withdrawal;   Time intervals apply to subcutaneous heparin used in thromboprophylactic doses; a APTT and/or ACT within normal range with therapeutic use of unfractionated heparin; b Applies only if platelet count and coagulation tests are normal; c Check platelet count if heparin therapy >4 days; d The second postoperative dose of LMWH should occur >24 h after the first dose. Apply guidelines for therapeutic dosing for twice-daily intermediate doses; e Administer first postoperative dose of LMWH after catheter withdrawal; f Measure prothrombin time/INR before neuraxial block placement. No specific values are stated in American Society of Regional Anesthesia guidelines.

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Table 2 Guidelines from national anesthetic societies for the timing of neuraxial anesthesia in patients receiving antiplatelet drugs and antifibrinolytics Aspirin Clopidogrel Ticlopidine GIIb/IIIa inhibitors: Abciximab* before NB/CW after NB/CW Tirofiban or epifibatide* before NB/CW after NB/CW Fibrinolytics*

Austria11

Belgium12

France13

Germany14

Netherlands15

Spain16

United States5

2 days spinal, 3 days epidural 7 days 10 days

No CIa

No CI

No CI

—c

No CI

No CI

7 days 10 days

CI CI NR

7 days 10 days CI

—c — CI

NR (7 days) NR (10 days) NR

7 days 14 days CI

48 h 4h

24-48 h 2-4 h

24-48 h —

— —

— —

24 h —

(48 h) —

8h 4h Not indicated

8-10 h 2-4 h CI d

24 h — CI

— — CI

— — CI

8h — 24-36 he (before NB/CW) 4 hf (after NB/CW)

(8 h) — NRg

b

CI: contraindication; CW: catheter withdrawal; NB: neuraxial block; NR: not recommended. * Time intervals in brackets are quoted by individual societies for normalization of platelet function after discontinuing drug. Timing interval before or after neuraxial block / catheter removal; a Advise avoid neuraxial blocks until anticoagulant effects have resolved following coadministration with glycoprotein IIb/IIIa inhibitors; b Omit longer-acting anticoagulant 24 h prior to neuraxial block/catheter withdrawal if combined with aspirin for perioperative thromboprophylaxis. Administer LMWH or fondaparinux between 36-42 h before or after neuraxial block/catheter withdrawal; c No specific time-intervals stated. If evidence of a bleeding tendency exists, wait P 10 days prior to NB; d If a neuraxial catheter is inserted, then laboratory values including fibrinogen ± thromboelastography should be normal prior to catheter withdrawal; e Coagulation tests including fibrinogen ± thromboelastography is advised prior to NB/CW; f If bloody puncture, then advise delay administering fibrinolytic P 24 h; g Use in exceptional circumstances with frequent neurological monitoring (time intervals for monitoring 6 2 h between checks). Suggest checking fibrinogen level prior to catheter withdrawal and restarting fibrinolytic at least 10 days after neuraxial block.

Table 3 Guidelines from national anesthetic societies for the timing of neuraxial anesthesia in patients receiving fondaparinux and thrombin inhibitors Austria11 Fondaparinux before* 36 h after* 4h Thrombin inhibitors Hirudins before* 10 h 4h after* Melagatran before* 8h 4h after* Argatroban before* — — after*

Belgium12

France13

Germany14

Netherlands15

Spain16

United States5

36 ha 12 h

NR — —

36-42 h 6-12 h

— —

36 h 6-12 h (NB)/12 h (CW)

— —

8-10 h 2-4 h

CI — —

8-10 h 2-4 h

— —

24 h 6h

— —

8-10 h 2-4 h

— —

— —

— —

8-10 h 2-4 h

—

— —

— —

4 hd 2h

— —

— —

— —

b

c c

CI: contraindication; NR: not recommended. * Timing interval before or after neuraxial block / catheter withdrawal; a Increase time interval for dosing after catheter withdrawal if creatinine clearance <50 mL/min; b Applies for dose 62.5 mg day. Neuraxial blockade is contraindicated for therapeutic doses (5-10 mg/day); c Only with single-shot atraumatic neuraxial block placement and no neuraxial catheter; d Prolong time intervals pre- and post-neuraxial block or catheter withdrawal in patients with hepatic impairment.

dogrel, ticlopidine), glycoprotein IIb/IIIa inhibitors, and direct thrombin inhibitors. Relevant pharmacologic data for individual drugs, based on non-obstetric patients, are summarized in Table 4.

Heparin Unfractionated heparin (UFH) is a heterogeneous mixture of polysaccharide chains of varying lengths (3-30 kDa). UFH produces its anticoagulant effect by binding

196 Table 4

Neuraxial anesthesia with anticoagulant drugs Pharmacologic data on individual anticoagulants and antithrombotics (based on non-obstetric patients)

Drug

Route of administration

Mode of action

Onset of action

Elimination half-life

Heparin

s.c., i.v.

Binding to ATIII

within 2 h (s.c.), immediate (i.v.)

LWMH

s.c.

Binding to ATIII

approximately 3-4 h

Warfarin

oral

within 90 min

Aspirin

oral

rapid (with 160 mg dose)

30 min

Fondaparinux

s.c.

within 2 h

17 h

Clopidogrel

oral

within 5 h

Ticlodipine

oral

7.5 h (of main metabolite) 20-50 h

Abciximab

i.v.

Eptifibatide

i.v.

Tirofiban

i.v.

Hirudins

s.c., i.v.

Inhibit c-carboxylation of factors II, VII, IX, X Irreversible inhibition of COX-1 Selective inhibition of factor Xa Inhibit ADP-induced platelet aggregation Inhibit ADP-induced platelet aggregation Inhibition of fibrinogen binding to GPIIb/IIIa receptors. Inhibition of fibrinogen binding to GPIIb/IIIa receptors Inhibition of fibrinogen binding to GPIIb/IIIa receptors Direct thrombin inhibitors

30, 60, 150 min (25 IU/kg, 100 IU/kg, 400 IU/kg) 3-6 h, dose-independent, prolonged in renal failure. 36-42 h

Argatroban Ximelagatran

i.v. oral

Direct thrombin inhibitor Direct thrombin inhibitor

1-8 h maximal effect 2 h after i.v. bolus

10-30 min

within 15 min

2-3 h

maximal effect within 5 min

1.8 h

maximal effect: i.v. bolus 10 min, i.v. infusion 3-6 h, s.c.=2-3 h 1-3 h (with i.v. infusion) maximal effect in 1.6-1.9 h

i.v. = 60 min, s.c.: 120 min (bivalirudin: i.v.: 25 min) 40-50 min 3-5 h

AT: Antithrombin; COX: cyclooxygenase; GP: glycoprotein.

to anti-thrombin III (ATIII), which interacts with thrombin (factor IIa), factor Xa, XIIa, XIa, IXa and kallikrein. Due to physiological changes during pregnancy, PK and PD differ significantly between the pregnant and nonpregnant population. Brancazio et al. reported lower AUC, lower peak plasma concentrations, shorter time to peak plasma concentrations (113 vs. 222 min), lower peak changes in activated partial thromboplastin time (APTT) and shortened times to peak changes in APTT (137 vs. 230 min) in third-trimester pregnant patients who received subcutaneous heparin compared to nonpregnant controls.19 Chunilal et al. similarly observed more attenuated in vitro APTT responses following UFH in plasma in third-trimester pregnant patients than in non-pregnant controls.20 These differences probably relate to a physiological increase in glomerular filtration rate, which increases drug clearance, and an increase in non-specific protein binding and plasma volume with advancing gestation (which contributes towards an increase in the volume of distribution of UFH). Consequently UFH dosing and/or frequency may need to be increased as pregnancy advances in order to maintain the required therapeutic effect and to compensate for the observed heparin resistance in pregnant patients.

Current recommendations for timing between administration of heparin and neuraxial anesthesia are outlined in Table 1. All national guidelines emphasize the need for normal APTT and/or activated coagulation time before neuraxial anesthesia. Obstetric anesthesiologists are most likely to encounter patients receiving subcutaneous UFH for thromboprophylaxis before delivery. Guidelines from a number of anesthetic societies relating to patients receiving subcutaneous UFH for thromboprophylaxis are outlined in Table 1. Importantly, pregnant patients will often be on higher doses due to pregnancy-induced heparin resistance.

Low-molecular-weight heparins LMWHs have become the most commonly used anticoagulants for prophylaxis and treatment of venous thromboembolism in the antenatal and postpartum periods. The advantages of LMWHs compared with UFH include a lower incidence of heparin-induced thrombocytopenia and osteoporosis and less frequent injections.21 LMWHs are depolymerised porcine mucosal heparin preparations; the molecular weight of LMWH can vary between 4-8 kDa. LMWHs act by binding with ATIII, which augments the inhibitory effect of ATIII on

A.J. Butwick, B. Carvalho

197

thrombin, activated factor Xa, FIXa, FIIa and kallikrein by a factor of P1000.22 LMWHs also inhibit FVIIa/tissue factor (TF) complex formation,23 induce the release of tissue factor pathway inhibitor (TFPI) and augment the inhibitory effect of TFPI on FVIIa/ TF complex formation.24 The PK-PD properties of LMWHs are heterogeneous due to the different molecular, structural and functional properties among drugs in this class. These variations result in significant differences in pharmacologic properties of each product. Anti-Xa activity assays are used to estimate the PD of LMWHs and monitor treatment efficacy, but results may vary due to individual differences in assay techniques. Thus, data presented in studies assessing anti-Xa and anti-IIa specific activity must be reviewed cautiously as assay techniques are not standardized.25 The bioavailability of LMWHs is >90%, and t1/2 values are generally twice as long as for UFH. A number of studies have assessed the PK of LMWHs in pregnant patients during the antenatal and postpartum periods. Norris et al. investigated patients undergoing thromboprophylaxis with subcutaneous tinzaparin; lower levels of therapeutic activity (anti-Xa levels >0.1 IU/ mL) were reported at 36 weeks compared to 24 weeks of gestation, with peak anti-Xa levels 4 h post-injection.26 Crowther et al. reported peak anti-Xa levels at 90-150

Table 5

min in pregnant patients receiving subcutaneous reviparin (4900 anti-Xa units; once a day).27 Anti-Xa levels were extremely low 24 h post-injection, and no evidence of bioaccumulation was reported. Anti-Xa levels were also highly correlated with patient weight (P <0.001). Sephton et al. assessed the PK of subcutaneous dalteparin (5000 units/day) in pregnant patients at 12, 24 and 36 weeks, and noted peak post-injection anti-Xa levels 4 h post-injection.28 AUC was lower in pregnancy at all gestational ages than in non-pregnant patients, with the lowest reading at 36 weeks’ gestation. Blomback et al. studied the PK of subcutaneous dalteparin (5000 units/day) in pregnant women at 32-35 weeks and reported that t1/2 values were 3.9-4.9 h.29 Several studies have assessed the PK of subcutaneous enoxaparin in pregnant and postpartum patients. Casele et al. investigated the PK of subcutaneous enoxaparin (40 mg daily) during three different time periods (12-15 weeks, 30-33 weeks and 6-8 weeks postpartum) (Table 5),30 and Lebaudy et al. assessed alterations in the PK of enoxaparin during pregnancy and following delivery using a population-based analysis (Table 6).31 Both studies reported that enoxaparin clearance does not significantly increase after the 1st trimester, which is consistent with an increase in glomerular filtration rate observed up to 16 weeks.30,31

Pharmacokinetic parameters for subcutaneous enoxaparin 40 mg/day in pregnant patients

Concentration 12 h post-injection (IU/mL) Maximum concentration (IU/mL) Time to maximum concentration (min) Area under plasma activity vs. time curve (IU/mL/min) Clearance (mL/min) Volume of distribution of drug at steady state (L) Mean residence time (min)

12-15 weeks’ gestation

30-33 weeks’ gestation

6-8 weeks’ postpartum

P value

0.09 ± 0.09 0.46 ± 0.08 185 ± 46 297 ± 79

0.16 ± 0.10 0.40 ± 0.08 229 ± 118 384 ± 158

0.19 ± 0.09 0.57 ± 0.09 192 ± 53 435 ± 118

<0.05*,  <0.05*,à NS <0.05*

14.6 ± 4.9 4.0 ± 0.9 287 ± 56

11.7 ± 3.7 3.7 ± 0.9 325 ± 44

10.0 ± 3.6 3.1 ± 1.0 316 ± 32

<0.05*,  <0.05* NS

Values are mean ± SE. * 12-15 weeks’ gestation vs. postpartum period;   12-15 weeks’ gestation vs. 30-33 weeks’ gestation; à 30-33 weeks’ gestation vs. postpartum period.30

Table 6

Pharmacokinetic data for enoxaparin Clearance (L/h)

Non-pregnant 11 weeks 21 weeks 29 weeks 34 weeks 38 weeks 2 days postpartum 13 days postpartum

0.52 0.74 0.77 0.79 0.82 0.80 0.71 0.71

Volume of distribution (L) 7.30 7.25 7.59 7.83 11.70 11.84 11.90 5.58

Predicted peak Anti-Xa activity (IU/mL) 40 mg/day (prophylactic)

1 mg.kg-1.12h-1 (therapeutic)

0.54 0.42 0.40 0.39 0.32 0.32 0.36 0.51

1.22 0.94 0.94 0.94 0.90 0.92 0.97 1.09

Anti-Xa activities correspond to prophylactic dosing regimen (40 mg once daily) and therapeutic dosing regimen (1 mg/kg/day normalized for body weight). Values for volume of distribution and clearance were adjusted for exponential intersubject variability; Weeks correspond to gestational age.31

198 Current recommendations for timing between administration of LMWH and neuraxial anesthesia are outlined in Table 1. The metabolism and clearance vary between different LMWH drugs in the non-pregnant population. LMWHs are predominately eliminated by the renal system following first-order kinetics. Patients with decreased renal function require cautious dosing of LMWHs. The assessment of anti-Xa levels to determine bleeding risks in patients receiving LMWHs is controversial. Although excessively high anti-Xa levels are associated with an increased risk of bleeding, lower anti-Xa levels have not been shown to be a good predictor of bleeding risk and antithrombotic efficacy in dose ranges for thromboprophylaxis.32 In addition, individual LMWH preparations have varying effects on hemostatic parameters in thromboprophylactic doses following cesarean delivery.33 It is uncertain whether the differences in hemostatic effects are associated with relevant differences in clinical outcomes.

Warfarin Warfarin is the most commonly used vitamin-K antagonist in clinical practice. It produces its anticoagulant effect by interfering with c-carboxylation of glutamate residues (G1a) on the N-terminal regions of vitamin K-dependent proteins (factors II, VII, IX and X). Warfarin is highly water-soluble, rapidly absorbed from the gastrointestinal tract, bound to plasma proteins and rapidly accumulates in the liver. The dose response can differ between subjects.34 Genetic and environmental factors (drugs, diet and disease states) also affect the PK characteristics of warfarin.35 Prothrombin time is commonly used to monitor its anticoagulant effects. At the initiation of warfarin therapy, the prothrombin time is predominately affected by depression of factor VII, which has the shortest half-life (5 h) of the vitamin-K dependent factors.36 The antithrombotic effect of warfarin follows reduction of prothrombin, which has a longer half-life (60-72 h). Current recommendations for neuraxial anesthesia in patients receiving warfarin are outlined in Table 1. The PK-PD of warfarin in pregnancy has been little investigated. One study evaluated warfarin dosage in postpartum patients compared to non-pregnant patients.37 Postpartum patients required significantly longer times and higher doses of warfarin to attain therapeutic levels of anticoagulation. Higher factor II, VII and X levels reported in the postpartum period may explain the need for higher therapeutic warfarin dosing in this subpopulation.

Aspirin Low-dose aspirin irreversibly inhibits platelet function by platelet cyclooxygenase-1 inhibition, which reduces production of thromboxane A2 (vasoconstrictor and

Neuraxial anesthesia with anticoagulant drugs platelet aggregator). Aspirin has a half-life of 15-20 min but has a long duration of action (7-10 days), consistent with the normal lifespan of platelets.38,39 A PK study of aspirin 75 mg in pregnant patients reported slower uptake and a lower peak level than in non-pregnant controls.40 No significant differences in PK were observed between patients at 27-29 weeks compared with patients at 36-38 weeks. Orlikowski et al. reported adequate in vivo hemostasis in pregnant patients after aspirin ingestion (600 mg) using thromboelastography.41 Kinouchi et al. observed that ADP-induced platelet aggregation was decreased in pregnant patients receiving antiplatelet therapy (aspirin 40 mg/day + dipyridamole 150 mg/day), but remained within normal range; prothrombin times and PTT values were also not prolonged.42 In the majority of cases, no special precautions are required for performing neuraxial anesthesia in patients receiving aspirin (Table 2).

Fondaparinux Fondaparinux is a synthetic pentasaccharide that belongs to a new class of anticoagulants with selective inhibition of factor Xa. Fondaparinux therapy may be considered in parturients with heparin-induced thrombocytopenia or severe cutaneous allergic reactions to heparin. Fondaparinux acts by binding to antithrombin with high affinity which leads to a 300-fold increase in factor Xa inhibition.43 The bioavailability of fondaparinux is 100% following subcutaneous administration, and peak plasma levels and AUC are both linearly related to dose. Cmax levels are achieved at 2 h following subcutaneous injection, but half Cmax is reached within 25 min of administration. Fondaparinux is primarily eliminated via the kidneys; the elimination half-life is dose-independent. Prophylactic fondaparinux administration in pregnant patients has been reported, but without details of anesthetic management.44,45 An ex vivo study assessing the placental transfer of high therapeutic doses of fondaparinux reported no evidence of placental transfer,46 although Demple et al. reported measurable anti-Xa levels in umbilical cord blood, which suggests placental transfer had occurred.47 Current recommendations for neuraxial anesthesia in patients receiving fondaparinux are outlined in Table 3.

Thienopyridines (clopidogrel, ticlopidine) Thienopyridines are indicated for thromboprophylaxis to prevent coronary stent thrombosis following percutaneous coronary intervention. Clopidogrel and ticlopidine are anti-platelet drugs that selectively inhibit ADP-induced platelet activation and aggregation. They are transformed to active metabolites in the liver. Both drugs act by irreversibly binding to P2Y12 receptors (which reduces ADP-induced activation of glycoprotein IIb/IIIa complexes), thrombin receptor agonist peptide (TRAP)-induced fibrinogen binding and P-selectin on

A.J. Butwick, B. Carvalho platelet membranes. The anti-platelet effect of thienopyridines affects between 60-70% of ADP receptors. Clopidogrel has a more favorable side-effect profile than ticlodipine, which may be associated with aplastic anemia, thrombocytopenia and thrombotic thrombocytopenic purpura. Combination therapy (aspirin + clopidogrel or ticlodipine) is often administered for patients requiring thromboprophylaxis following coronary stent placement due to an additive effect on platelet inhibition.48 Following oral administration of clopidogrel (200-600 mg), inhibition of ADP-induced platelet aggregation is maximal within 5 h.49 This inhibition by daily dosing with clopidogrel or ticlodipine reaches steady-state after six days (52% and 43% inhibition by 75 mg clopidogrel daily and 250 mg ticlodipine twice daily respectively).50 Bleeding time reverts to normal seven days after stopping clopidogrel therapy.49 Clopidogrel is rapidly absorbed from the gastrointestinal tract following oral ingestion, extensively metabolized by the cytochrome P450 system and is six times more potent than ticlodipine. Inactive metabolites are renally excreted at a constant rate, which validates the linear PK profile of clopidogrel. The Tmax of clopidogrel is 0.8-1.0 h, and the terminal t1/2 of the main circulating metabolite is approximately 7.5 h.51 A dose-proportional increase in Cmax occurs with doses between 50-150 mg clopridogrel.52 Ticlopidine has an oral bioavailability of up to 90%, and may initiate platelet inhibition as soon as 1 h after oral administration.53 After discontinuation of ticlodipine, platelet function recovers slowly over 3-8 days.53,54 Ticlodipine has non-linear PKs, and its clearance decreases with repeat dosing.55 To our knowledge, no studies have investigated PKPD of clopidogrel or ticlodipine in pregnant patients, and only one report has previously described epidural analgesia for labor after discontinuing clopidogrel 10 days before delivery.56 Current recommendations for non-pregnant patients receiving clopidogrel or ticlodipine requiring neuraxial anesthesia are outlined in Table 2.

Glycoprotein IIb/IIIa inhibitors The expression of functionally active integrin aIIbb3 (GPIIb/IIIa) on the platelet surface is the final common pathway of platelet aggregation, and has become an important target for the development of novel antiplatelet drugs. GPIIb/IIIa inhibitors prevent the binding of fibrinogen to GPIIb/IIIa complexes, and are normally administered for prevention of coronary stent thrombosis following percutaneous coronary intervention. These drugs are often administered in combination with aspirin, unfractionated heparin or clopidogrel. Three GPIIb/IIIa drugs are currently available (abciximab; eptifibatide; tirofiban), which are normally administered as an intravenous bolus followed by an infusion. Abciximab is a chimeric (human/murinic) IgG Fab fragment with a relatively quick onset of action (peak

199 effect = 2 h following bolus administration of 0.25 mg/kg).57 Platelet aggregation returns to P50% of baseline within 24-48 h of terminating the intravenous infusion.57 Eptifibatide is a cyclic heptapeptide with less affinity for platelet receptors than other GPIIa/IIIb receptors. It is a competitive inhibitor of platelet aggregation and is predominately cleared renally. Tirofiban is a peptidomimetic nonapeptide with intermediate affinity for platelet receptors. The onset of action and platelet-bound half-life are shorter than for abciximab. Tirofan undergoes both renal and biliary clearance. All three GPIIb/IIIa antagonists have been reported to cause thrombocytopenia, and platelet counts should be monitored closely in all those receiving these agents.58,59 Neuraxial anesthesia is generally not recommended in patients receiving GPIIb/IIIa antagonists (Table 2).

Direct thrombin inhibitors Indirect thrombin inhibitors, such as heparin, require a plasma co-factor to exert their effect. Direct thrombin inhibitors inhibit free- and clot-bound thrombin via the active site of thrombin (univalent inhibitors) or via the fibrinogen-binding site (bivalent inhibitors). Direct thrombin inhibitors do not have the limitations of heparins (notably thrombocytopenia), and are indicated in a number of different settings: thromboprophylaxis for venous thromboembolism, acute management of unstable angina or myocardial infarction, and prevention of embolic stroke in atrial fibrillation. Bivalent direct thrombin inhibitors: The hirudins are commercially available bivalent direct thrombin inhibitors that include, recombinant variants (lepirudin, desirudin) and hirudin analogues (bivalirudin). Hirudins are indicated for heparin-induced thrombocytopenia (HIT) complicated by thrombosis, as well as thromboprophylaxis following orthopedic surgery.60 There are several case reports of the successful use of recombinant hirudin (subcutaneous61,62 and intravenous63) in pregnant patients with HIT. Hirudins undergo renal elimination and accumulate in patients with renal insufficiency. Antibodies can develop in up to 40% patients treated with lepirudin, and anaphylaxis can develop in patients with antibodies who are re-exposed to hirudin. Unlike recombinant hirudins, bivalirdun only undergoes 20% elimination by the kidneys, and is not immunogenic. No current antidote is available to reverse the effect of hirudin or its derivatives, therefore irreversible binding is a major therapeutic limitation. Close APTT monitoring is recommended due to the high bleeding risk.64 Univalent direct thrombin inhibitors: Argatroban binds reversibly to the active site of thrombin, and has minimal effects on related serine proteases. Argatroban is approved for use in patients with HIT or HIT with

200 thrombosis. Cautious dosing is necessary in patients with hepatic impairment as metabolism is significantly influenced by hepatic function. APTT should be monitored to assess anticoagulant activity.65 The rapid elimination profile of argatroban is potentially useful in the setting of induction of labor and regional anesthesia in obstetric patients.66 Current recommendations for timing between administration of direct thrombin inhibitors and neuraxial anesthesia are outlined in Table 3. In conclusion, anticoagulant and antithrombotic drugs are increasingly indicated for the thromboprophylaxis and treatment of thrombotic complications during pregnancy and the prevention of pregnancy loss in high-risk conditions such as thrombophilia. Many antithrombotic and anticoagulant agents are currently available. Novel anticoagulants and clinical applications in pregnant patients continue to evolve and pose unique challenges to the anesthesiologist.67 Although anesthetic societies have developed guidelines to assist anesthesiologists, there are many uncertainties regarding the optimal timing of neuraxial anesthesia, in particular for pregnant patients receiving anticoagulants. The decision to proceed with neuraxial analgesia or anesthesia in parturients receiving these drugs should be individualized and based on careful risk-benefit consideration, and it is important to be familiar with PK-PD data of individual drugs as well as national guidelines.

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