Anticoagulation and the Pregnant Patient

AC Forum Master Class Nathan Clark, Pharm D, FCCP, BCPS

Kaiser Permanente Colorado

Conflicts of Interest

• I have no relevant financial conflicts of interest to disclose.

Overview

1. Pathophysiology of thromboembolism in pregnancy

2. Pharmacology of preferred anticoagulants 3. Pregnancy planning in chronically

anticoagulated women 4. Anticoagulation for pregnant women with acute

deep vein thrombosis (DVT) or pulmonary embolism (PE)

5. Prevention of DVT/PE during pregnancy and postpartum

Thromboembolism in Pregnancy

• Venous stasis – Compression inferior vena cava – Decreased venous flow velocity

• Vascular injury • Hypercoagulability

– Increased clotting factors VII, VIII, and X – Increased von Willebrand factor and fibrinogen – Decrease in protein S

American College of Obstetricians and Gynecologists; September 2011; Practice Bulletin Number 123

Anticoagulants in Pregnancy During Pregnancy

Preferred Medications Medications we use sometimes

Medications to Avoid

Enoxaparin (Lovenox®) Warfarin Dabigatran (Pradaxa®)

Dalteparin (Fragmin®) Fondaparinux (Arixtra®) Rivaroxaban (Xarelto®)

Tinzaparin (Innohep®) Apixaban (Eliquis®)

Unfractionated heparin Edoxaban (Savaysa®)

Breast Feeding Preferred Medications Medications to Avoid

Warfarin Dabigatran (Pradaxa®)

Low-molecular-weight heparin Rivaroxaban (Xarelto®)

Unfractionated heparin Apixaban (Eliquis®)

Fondaparinux (Arixtra®) Edoxaban (Savaysa®)

Anticoagulants to Avoid (usually) • Warfarin is teratogenic (category X)

– Exposure 6 to 12 weeks gestation: collagen malformation (nasal hypoplasia, stippled epiphyses)

– 3rd trimester exposure: fetal bleeding, CNS development – Miscarriage and spontaneous abortion (doses > 5mg/day ↑risk)

• Fondaparinux (category B)

– Long half-life (19 hours) – Found in umbilical chord blood samples

• Direct-acting oral anticoagulants (category B/C)

– Not known teratogens but cross placenta – Rivaroxaban and apixaban in breast milk

Obstet Gynecol. 2014 Jun;123(6):1256-61 Am J Obstet Gynecol. 2015 Nov;213(5):710 J Thromb Haemost. 2016 Jul;14(7):1436-41

N Engl J Med. 2004 Apr 29;350(18):1914-5.

Mechanism of Action

LMWH

Fondaparinux

Xa

1

AT AT

2 3

AT

4

AT Thrombin

Xa

1

AT AT

2 3

AT

4

AT Thrombin

Xa

1

AT AT

2 3

AT

4

AT Thrombin

Unfractionated Heparin

Nutescu E, Dager W. Heparin, low molecular weight heparin, and fondaparinux. In: Gulseth M, ed. Managing anticoagulation patients in the hospital. Bethesda, MD:

ASHP; 2007:177-202.

Mechanism of Action

Intrinsic system (surface contact)

XII

XI

Tissue factor

VIII VIIIa

Extrinsic system (tissue damage)

V Va

IX VII

X

II

Fibrinogen Fibrin

(Thrombin)

XIa

VIIa

aPTT PT/INR

Warfarin

LMWH Partial LMWH Inhibition Heparin

Clot

IXa

XIIa

Xa

IIa

Comparative Pharmacology UFH LMWH Implication

Half life 1-1.5 hr 4-7 hr Faster UFH offset via IV infusion

Onset 3-4 hr 3-5 hr None

Monitoring aPTT or anti-Xa Platelet count

Platelet count Renal function

Less LMWH monitoring

Variability of response Yes Relatively low

Coagulation testing rarely indicated for LMWH (other

than MHV)

HIT Med/OB: <1% Med/OB: <0.1% Not a primary consideration in OB

Reversal Agent Protamine (100%) Protamine (~50%)

UFH reversibility in labor/delivery

Osteoblast Inhibition

Bone mineral density

Bone mineral density

+ UFH fracture risk +/- LMWH fracture risk

Managing Mechanical Heart Valves in Pregnancy

• Women with mechanical heart valves (MHVs) are very high risk for thrombosis and pregnancy complication

• Preconception planning is mandatory • The optimal anticoagulant strategy has not

been defined

BMJ. 2002 Nov 23; 325(7374): 1228–1231

MHV Complications in Pregnancy

Arch Intern Med. 2000 Jan 24;160(2):191-6. Clin Med Insights Cardiol. 2016 Feb 10;10:11-7

Anticoagulation Management in MHV

Preconception First Trimester Second Trimester Third Trimester

Labor and delivery

Warfarin

UFH/LMWH

BMJ. 2002 Nov 23; 325(7374): 1228–1231

UFH and LMWH Dosing for MHV

Medication Initial Dose Target* Timing UFH 250U/kg SC BID Anti-Xa

0.5 to 0.7 u/ml Mid-interval

6 hr Enoxaparin 1mg/kg SC BID** Anti-Xa

1.0 to 1.2 u/ml Peak

3 – 5 hr Dalteparin 100IU/kg SC

BID** Anti-Xa

0.8 to 1.0 u/ml Peak

3 – 5 hr *Anti-Xa examples are based on targeting the upper ½ of the therapeutic range for DVT/PE treatment. Verify with your laboratory the appropriate concentration curves and therapeutic reference ranges. ** The VTE treatment doses for LMWH are the minimum acceptable doses for patients with normal renal function. Do not reduce dose below these levels.

Labor and Delivery for MHV

• Stop UFH/LMWH 24 hours prior to induction – IV UFH can be substituted in very high risk (e.g.

AVR/MVR) – stop 4 hours prior to induction

• Normal aPTT prior to epidural (UFH) • Restart UFH/LMWH at previous dose

– 12 hours after vaginal delivery – 24 hours after cesarean birth

• Bridge back to warfarin

Management of Long Term Anticoagulation for DVT/PE History

• Anticoagulation options: – Continue oral anticoagulation (warfarin/DOAC)

with frequent pregnancy testing OR – Transition to LMWH (preferred to UFH)

• Initial dosing is the same as MHV:

– Twice daily dosing is still preferred during pregnancy due to enhanced renal clearance

Acute DVT/PE During Pregnancy

• Uncomplicated DVT can be treated as an outpatient

• PE should be monitored as inpatient for at least 24 hours

• Anticoagulation options remain UFH and LMWH – LMWH preferred over UFH as outpatient

Monitoring Therapeutic UFH/LMWH

• Therapeutic UFH always requires monitoring during long term use – Anti-Xa or aPTT every 3 days until therapeutic then every 1

to 4 weeks – Adjust dose by 2000 to 4000 units per day – Target anti-Xa 0.35-0.7u/ml

• Therapeutic LMWH anti-Xa monitoring is optional for VTE – Periodic anti-Xa monitoring every 4 weeks , or – Adjust LMWH dose according to weight gain, or – No LMHW dose adjustment is also an option

Labor and Delivery for DVT/PE

• Similar to MHV, but rarely a need for IV UFH – Possible exceptions:

• Very recent (within 4 weeks) acute DVT/PE • Profound thrombophilia and extensive VTE history

• Bridge back to warfarin, or • Restart DOAC if not breastfeeding • Duration of therapy for first, pregnancy-

related DVT/PE is 3 to 6 months AND at least 6 weeks postpartum

VTE Prophylaxis

No Personal History of VTE Description Antenatal Postpartum Heterozygous FVL or PT 20210 Clinical vigilance Clinical vigilance

Confirmed Protein C or S deficiency Prophylactic Yes

Homozygous FVL or PT 20210 Confirmed AT deficiency Multiple traits

Prophylactic or Intermediate Yes

Antiphospholipid Antibody Syndrome (APLAS)

Prophylactic or Intermediate UFH +

aspirin 81mg Yes

VTE – venous thromboembolism; FVL – factor V Leiden; PT 20210 – prothrombin G202210A mutation; AT – antithrombin; UFH – unfractionated heparin Clinical vigilance = thorough patient education and timely objective investigation of DVT/PE symptoms

Chest 2012;141:e691S-e736S American College of Obstetricians and Gynecologists; September 2011; Practice Bulletin Number 123

http://www.guideline.gov/content.aspx?id=25312 accessed 03/24/15

Why UFH for APLAS?

• Meta-analysis of women with APLAS found the combination of UFH and aspirin reduced the risk of pregnancy loss by 54%

• Quality of the evidence was not high, but this remains the only data to support an anticoagulant for prevention of miscarriage in any thrombophilia population

Cochrane Database Syst Rev. 2005 Apr 18;(2):CD002859

VTE Prophylaxis Positive Personal History of VTE Description Antenatal Postpartum

Single prior provoked VTE unrelated to estrogen or pregnancy Clinical vigilance Yes

Single prior VTE provoked by estrogen or pregnancy Prophylactic Yes

Prior VTE associated with thrombophilia, not receiving long-term anticoagulation

Prophylactic or Intermediate Yes

Unprovoked or multiple VTE, not receiving long-term anticoagulation Intermediate Yes

VTE – venous thromboembolism; Clinical vigilance = thorough patient education and timely objective investigation of DVT/PE symptoms

VTE Prophylaxis Regimens

Description Drug Dose

Prophylactic

Heparin 5,000 units q12h

Enoxaparin 40mg QD

Dalteparin 5,000 units QD

Tinzaparin 4,500 units QD

Intermediate

Heparin 120 units/kg q12h titrated to mid-interval anti-Xa 0.1 to 0.3 u/ml

Heparin 5,000 units q12h (1st trimester) 7,500 units q12h (2nd trimester) 10,000 units q12h (3rd trimester)

Enoxaparin 40mg q12h

Dalteparin 5,000 units q12h

Labor and Delivery with VTE Prophylaxis

• Patient should discuss induction option with OB provider – Timing is less critical – Potential implications with anesthesia options

• Prophylactic UFH/LMWH stop at least 12 hours prior to epidural

• Intermediate and UFH/LMWH stop at least 24 hours prior to epidural

American College of Obstetricians and Gynecologists; September 2011; Practice Bulletin Number 123

http://www.guideline.gov/content.aspx?id=25312 accessed 03/24/15

Labor and Delivery with VTE Prophylaxis

• Prophylactic UFH/LMWH can be restarted: – 6 to 12 hours after vaginal or cesarean delivery – At least 2 hours after epidural withdrawal

• Intermediate UFH/LMWH can be restarted: – 12 hours after vaginal delivery – 24 hours after cesarean delivery

American College of Obstetricians and Gynecologists; September 2011; Practice Bulletin Number 123

Postpartum VTE Prophylaxis Regimens

• Continue VTE prophylaxis 6 weeks postpartum – Resume the antenatal regimen, or – Transition to warfarin (INR 2-3)

Chest 2012;141:e691S-e736S

References you need to manage anticoagulation in pregnancy

https://www.asra.com/advisory-guidelines/article/1/anticoagulation-3rd-edition