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UNIVERSITY OF SOUTH FLORIDA Making Life Better ® Diagnosis and Management of Venous Thromboembolic Disorders in Pregnancy Dr. Charles Lockwood Senior Vice President, USF Health Dean, Morsani College of Medicine Professor Ob/Gyn and Public Health

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UNIVERSITY OF SOUTH FLORIDA Making Life Better®

Diagnosis and Management of Venous Thromboembolic Disorders in Pregnancy

Dr. Charles LockwoodSenior Vice President, USF HealthDean, Morsani College of MedicineProfessor Ob/Gyn and Public Health

Making Life Better®

Conflict of Interest Disclosure Agreement

I have no financial interest or other relationships with industry relevant to the

topics being discussed.

Making Life Better®

Learning Objectives1) Understand the factors that render

pregnancy a pro- thrombotic state.2) Understand the work up of patients at risk

for acute pulmonary embolism.3) Know the evidence base for prevention

and treatment of VTE.

Making Life Better®

VTE in Pregnancy• Overall incidence is 1/1600

– DVT 0.71/1000 (70% antepartum; 30% postpartum),7-10 X rate over age-matched controls.

– PE 0.15/1000 (47% antepartum; 53% postpartum),15-35 X rate of age-matched controls.

• Risk highest first 6 wks postpartum (OR 11; 95%CI: 8-15), declines but still elevated at 7 to 12 wks (OR 2; 95% CI 1.5-3.1). Prevalence dropping in postpartum but increasing in antepartum period x 30 yrs.

Source: N Engl J Med. 2014;370(14):1307; Lancet. 2010 Feb 6;375(9713):500-12; J Thromb Haemost. 2010;8(5):998; Ann Intern Med. 2005;143(10):697

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Unique features of VTE in Pregnancy• Isolated pelvic vein thrombosis account for

11% of DVT in pregnancy vs. 1% in non-pregnant women.

• 90% of DVTs in pregnancy are left-sided.• PE accounts for 9.2% of maternal mortality;

AA women have 4X mortality vs. whites. • 75% of fatal PE’s occur after C-sections.

Source: Lancet. 2010 Feb 6;375(9713):500-12; New Engl J Med 2008; 359:2025-33; CMAJ. 2010;182(7):657. cdc.gov/mmwr/preview/mmwrhtml/ss5202a1.htm#tab3

Making Life Better®

VTE: How to DX and TX• Physiologic Regulation of Hemostasis

• Risk factors for VTE

• Diagnosis of VTE

• Treatment of VTE

• Prevention of VTE

Making Life Better®

Pregnancy-Associated Changes in Hemostatic and Fibrinolytic Proteins• Increase in Clotting Factors: 20 to 200% increase in

levels of fibrinogen and factors II, VII, VIII, IX, and X.• Decrease in Anticoagulant Activity: Protein S levels

decrease by 40%. • Increase in Anti-fibrinolytic activity: PAI-1 levels

increase two to three-fold in pregnancy; placental derived PAI-2 appears.

Source: Lancet. 2010 Feb 6;375(9713):500-12.

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Pregnancy-Associated Factors Predisposing to VTE

• Venous Stasis: Compression of iliac veins by uterus, of left iliac vein by right iliac artery, general venous dilation due to P4, NO, and PgI2, 50% decrease in lower extremity venous flow by 25 weeks.

• Vascular damage: Placentation, delivery

Source: Lancet. 2010 Feb 6;375(9713):500-12; New Engl J Med 2008; 359:2025-33

Making Life Better®

VTE: How to DX and TX• Physiologic Regulation of Hemostasis

• Risk factors for VTE

• Diagnosis of VTE

• Treatment of VTE

• Prevention of VTE

Making Life Better®

Risk Factors for VTE during Pregnancy

• Multiple births• Varicose veins/STP• Medical Complications (DM, IBD, UTIs, CRD)• Increased parity • Age ≥35 years• BMI ≥ 30 kg/m2

• Antenatal hospitalization > 3 days

Blood. 2013;121(19):3953; BMJ. 2013;347:6099

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Risk Factors for Puerperal VTE• Cesarean delivery (emergency)• Postpartum endomyometritis • Preeclampsia, IUGR and IUFD• Medical complications• Varicose veins/STP• Ob hemorrhage• BMI ≥ 30 kg/m2

Obstet Gynecol. 2014;123(5):987; Blood. 2014;124(18):2872

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Risk of maternal VTE for a given thrombophilia

Disorder VTE Risk No Hx VTE Risk (+) Hx % of VTE RR of VTE

FVL (heteroz.) 0.5%-1.2% 10% 40% 7X

FVL (homoz.) 4% 17% 2.2% 25X

PGM (heteroz.) <0.5% >10% 17% 9X

PGM (homoz.) 2 - 4% >17% 0.50% >25X

FVL/PGM 4.7% >20% 1-3% 84X

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Disorder VTE Risk No Hx

VTE Risk (+) Hx % of VTE RR of VTE

AT def activity < 60% 3-7% 40% 1% >100X

PC def activity < 50% 0.1-0.8% 4-17% 14% 13X

PS def free Ag < 55% 0.1% 0-22% 3% 5X

Sources: Best Pract Res Clin Haematol 2003; 16:243-59; ACOG Practice Bulletin #138. Thromboembolism in pregnancy. Obstet Gynecol 2013; 122:706

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VTE: How to DX and TX• Physiologic Regulation of Hemostasis

• Risk factors for VTE

• Diagnosis of VTE

• Treatment of VTE

• Prevention of VTE

Making Life Better®

Clinical Diagnosis of DVT• 90% False Positive rate with calf or thigh

tenderness and pain, erythema and edema.• Differential diagnosis includes cellulitis, ruptured

or strained muscle or tendon, trauma, ruptured popliteal (Baker’s) cyst, cutaneous vasculitis, superficial thrombophlebitis, and lymphedema.

Source: New Engl J Med 2008; 359:2025-33

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Studies to Diagnose DVT in Pregnancy

1) Serial Compression Color Doppler Venous Ultrasonography (VUS) on days 3 and 7: highly predictive of proximal vein DVT Sensitivity of 94.1% and FNR of 0.7%

2) Lower efficacy for isolated calf vein DVT (sensitivity 92.5%, specificity 98.7%).

Source: CMAJ. 2013 Mar;185(4):E194-200. Epub 2013; 27:415-20); Ann Intern Med. 2007;147(3):165.

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Studies to Diagnose DVT in Pregnancy

2) D-dimer: Study of 149 at risk pregnancies with DVT prevalence of 8.7%, SimpliRED D-dimer assay had efficacy of:• Sensitivity of 100% (77% to 100%)• Specificity of 60% (52% to 68%)• Negative predictive value of 100% (95% to 100%)

Source: (Chan et al. Ann Intern Med. 2007; 147:165-70)

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Imaging Studies to Diagnose DVT in Pregnancy

3) Venous Magnetic Resonance (MR) imaging efficiency is equivalent to VUS.

– Sensitivity in non-pregnant patients approaches 100%, Specificity 96%, NPV 100%, PPV 90%.

– May be very useful in cases of iliac DVT Source: European Radiology 2007; 17:175-81; J Vasc Surg. 1993;18(5):734.

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LEFt clinical prediction rule1) Symptoms in left leg (L for left), Calf circumference difference ≥2 cm (E for edema) & First trimester presentation (Ft for 1st tri.)2) Among patients presenting with 0, 1, and 2/3 variables, DVT was diagnosed in 0, 16, and 58%.

Source: Haematologica. 2013 Apr;98(4):545-8.

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Patient with Signs and Symptoms of DVT

Low riskpatient?

(-) D-dimer < 500 ng/m

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Clinical Diagnosis of Pulmonary EmbolismSymptoms of PE In pregnancy include:• Dyspnea (62%)• Pleuritic Chest pain (55%)• Tachycardia (54%)• Abn alveol.-art. grad >14 mmHg (41%)• Cough (24%) • Diaphoresis (18%)• Hemoptysis (8%)• Syncope (5%)

Source: Arch Intern Med 2002; 162:1170-5; Obstet Gynecol 2009; 114:124-9; Am J Obstet Gynecol. 1998;178(2):394.

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Ancillary tests for PE1) D-Dimers: Study of 37 at risk women found

sensitivity only 73% with low specificity (15%); also literature contains multiple false negative case reports

2) Compression VUS: Lower extremity DVT seen in 36%-82% of non-pregnant pts with PE

Sources: J Obstet Gynaecol 2009; 29:101-103; J Obstet Gynaecol 2008; 28:222-223; Thromb Res 2008; 121:705-7; Eur Clinics Obstet Gynaecol 2008; 3:31-4) & Eur J Vasc Endovasc Surg 2009; 37:225-31; Chest 1999; 116:903-8; Chest 2005; 128:1593-1600; Br J Radiol 1998; 71:1260-5

Making Life Better®

Ancillary tests for PE

3) EKG findings: RBBB, Right axis deviation, Q waves in lead III and aVF, S waves in lead I and aVL >1.5 mm, T wave inversions in leads III and aVF and/or new-onset A-fib.4) Echocardiographic findings: RV dilation and hypokinesis, Tricuspid regurgitation and PA dilation.

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Signs of Pulmonary Embolus5) Ventilation-Perfusion (V/Q): In setting of normal CXR, V/Q scan diagnostic in 75-93% of pregnant women vs. 64.3% for CTPA.

– Very low risk of subsequent VTE if normal– Sensitivity >85%, specificity > 95%, NPV 100%– Perfusion component alone has comparable efficacy

but lower fetal radiation

Sources: AJR 2009; 193:1223-7; J Nucl Med 2008; 49:1741-8; Eur Radiol. 2007 Oct;17(10):2554-60. Epub 2007 Mar 7.

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Signs of Pulmonary Embolus6) CT Pulmonary Angiography (CTPA): multi-detector-row machines yield false negative results < 1%:

– More diagnostic than V/Q when CXR is abnormal but technically inadequate in 17 to 28% of all cases.

– Other clinically significant findings found in 12-13% of patients including pneumonia and pulmonary edema

Sources: Eur Radiol. 2008;18(12):2709.; AJR 2010: 195:W214-22; Radiology. 2011; 258(2):590; Obstet Gynecol 2009; 114:124-9.

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Radiation Exposures CTPA vs. V/Q

Exposure CTPA V/Q

Fetus 0.003-0.131 mGy 0.32-0.74mGy

Maternal Breast 35.0 mGy 0.25 mGy

Source: Radiology. 2002;224(2):487; Lancet. 2010;375(9713):500

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V/Q vs. CTPA• If CXR Normal -V/Q preferred because it is more

diagnostic than CTPA, has lower breast radiation, and because of uncertainty over clinical import of subsegmental PE more commonly found on CTPA.

• If CXR Abnormal - CTPA preferred because it can r/o other life-threatening diagnoses (e.g., aortic dissection) and exposes fetus to less radiation than V/Q.

Source: (Lancet. 2010 ;375(9713):500-12; Leung AN, et al., Radiology, 2012; 262: 635-46)

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Patient with Signs and Symptoms of Acute PE

*If hemodynamically unstable consider TE-echo at bedside

Making Life Better®

VTE: How to DX and TX• Physiologic Regulation of Hemostasis

• Risk factors for VTE

• Diagnosis of VTE

• Treatment of VTE

• Prevention of VTE

Making Life Better®

Who to treat in PregnancyTherapeutic LMWH x 4 months (20 weeks)

followed by Prophylactic LMWH

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Therapeutic LMWH Dose• Dalteparin sodium (Fragmin) 200 U/kg s.q. once daily;

or 100 U/kg s.q., every 12 hrs. (up to 5,000 U) • Enoxaparin (Lovenox) 1 mg/kg up to 100 mg in s.q.,

every 12 hrs.• Titrate dose of LMWH to target anti-factor Xa levels of

0.6 to 1.0 IU/ml 4 hours after 3rd or 4th dose for twice daily Rx; or 1 to 2 IU/ml 4 hours after 2nd or 3rd dose for once daily Rx.

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Prophylaxis with LMWH Dose: Dalteparin: 5000 U s.q. once daily; or

enoxaparin: 40 mg s.q., once daily; adjust both to maintain anti-factor Xa levels at 0.1 –0.2 U/ml 4 hrsafter 3rd or 4th injection dose.

Risk of epidural anesthesia: due to reports of epidural hematomas associated with LMWH heparin therapy, such therapy should be discontinued at 36-37 weeks or earlier if delivery is anticipated, and unfractionated heparin therapy resumed to permit regional anesthesia

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Intrapartum Management:Patients on Unfractionated Heparin

Vaginal or cesarean delivery not accompanied by significant risks bleeding if procedure occurs > 6 hrsafter a prophylactic UFH dose, or > 12 hrs after prophylactic dose of LMWH or > 24 hrs after therapeutic dose of LMWH.

If patient on therapeutic UFH an aPTT should be checked pre-operatively. Protamine may be given to reverse a prolonged aPTT at the time of delivery.

Making Life Better®

Intrapartum Management (Con’t)

AT concentrates can be used in AT deficient patients in the peripartum period.

UFH or LMWH should be resumed 4-6 hours after a vaginal delivery and 8-12 hours after a cesarean delivery.

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Postpartum treatment

Condition Duration PE or Iliofemoral DVT in index pregnancy

4-6 months

DVT in index pregnancy or 12 weeks ATIII deficiency

DVT or PE in a prior pregnancyor other inherited thrombophilia

6 weeks

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Postpartum treatment

a) Warfarin can be initiated immediately post-partum, titrating dose to maintain INR at > 2

b) Because of Warfarin’s more rapid inhibitory effect on protein C compared with clotting factors, heparin shouldalways be maintained during the initial 5 days of Warfarintherapy and heparin should not be stopped until INR > 2 x 48 hrs.

Making Life Better®

VTE: How to DX and TX• Physiologic Regulation of Hemostasis

• Risk factors for VTE

• Diagnosis of VTE

• Treatment of VTE

• Prevention of VTE

Making Life Better®

ACOG recommendations prevention of postpartum VTE

• ACOG recommends pneumatic compression devices for all patients before, during and after C-section

• Low risk thrombophilia (LMWH if additional risk factors –C-section, prior VTE, FHx, BMI > 30)

• High risk thrombophilia (LMWH, - x 6 weeks if prior VTE) • No thrombophilia but prior VTE (LMWH)

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National Partnership for Maternal Safety has called for more aggressive use of pharmacological thromboprophylaxis in pregnancy.

• Patients with Antepartum Hospitalizations: Prophylactic heparin in al patients, not receiving LMWH, admitted to hospital > 72 hrs and not at risk for bleeding. If at risk for bleeding, patients should receive pneumatic compression devices in lieu of heparin.

• Patients with Vaginal Deliveries: Use intrapartum pneumatic compression devices with a history of VTE or thrombophilia followed by heparin based on RCOG or Padua criteria.

DʼAlton et al. Obstet Gynecol. 2016 Oct;128(4):688-98.

Making Life Better®

National Partnership for Maternal Safety has called for more aggressive use of pharmacological

thromboprophylaxis in pregnancy.• Patients with Cesarean Deliveries: All patients should

use pneumatic compression devices until fully ambulatory. Heparin thromboprophylaxis for women with risk factors based on RCOG or Caprini criteria.

• Given the challenges in consistently identifying women with risk factors and issues related to poor compliance with mechanical devices, hospitals may choose a strategy in which all women undergoing cesarean birth receive postoperative heparin thromboprophylaxis.”

DʼAlton et al. Obstet Gynecol. 2016 Oct;128(4):688-98.

Making Life Better®

VTE: How to DX and TX• Physiologic Regulation of Hemostasis

• Risk factors for VTE

• Diagnosis of VTE

• Treatment of VTE

• Prevention of VTE