Venous Thromboembolism: Risk Assessment and Prophylaxis

VTE Prophylaxis Venous thromboembolism (VTE) is a leading cause of maternal mortality and severe morbidity Maternal death from VTE is amenable to prevention Prophylaxis is the most readily implementable means of systematically reducing the maternal death rate Protocols in the UK has led to significant reduction in maternal death from VTE Strategies for preventing VTE require minimal resources and are easily implementable See Slide.

Key Elements in VTE Prophylaxis Bundles Risk assessment tools   Protocols for antenatal and postpartum prophylaxis  Suggested dosing schedule Anesthesia recommendations Key references International Guidelines Key papers This maternal safety bundle provides strategies for venous thromboembolism risk assessment and prophylaxis. The key elements in this bundle include management recommendations that apply to all obstetric patients including risk assessment tools, protocols for prophylaxis, dosage recommendations and recommendations for administration of anesthesia. For information on how to further implement and incorporate this bundle within the obstetric unit, please refer to the introductory section of this toolkit for an overview of important clinical considerations.

Risk Assessment All patients should be assessed for VTE risk multiple times in pregnancy including during: Presentation for prenatal care Hospitalization for an antepartum indication Delivery hospitalization (in-house postpartum) Discharge from a delivery hospitalization Prophylaxis can be based on risk factors or can be empiric The core concept of this set of management recommendations is that all obstetric patients should be assessed at multiple time points during pregnancy for thromboembolism risk. Appropriate prophylaxis of patients at risk for thromboembolism is the strategy most likely to reduce severe morbidity and mortality from this cause.

Risk Assessment Thromboembolism prophylaxis is a Joint Commission quality measures The Joint Commission states that all patients should receive VTE prophylaxis OR have documentation why no VTE prophylaxis was given Within a day of hospital admission Within a day of surgery The 2013 Joint Commission Specifications Manual for National Hospital Inpatient Safety Thromboembolism risk assessment and prophylaxis are important quality measures for all hospitalized patients including patients hospitalized for obstetric indications.

Risk Assessment Tools To aid clinicians and hospitals in providing prophylaxis, risk assessment tools have been developed.

Risk Assessment Tools Sources: Risk assessment tools were based on recommendations from major society guidelines Prenatal outpatient and postpartum discharge thromboprophylaxis are based primarily on American College of Chest Physicans and ACOG recommendations Inpatient prophylaxis is based primarily on RCOG recommendations Pharmacologic prophylaxis may be with unfractionated heparin (UFH) or low-molecular weight heparin (LMWH) Chest, Feb 2012; 141 ACOG Practice Bulletin No 123, 2011 See Slide.

Initial Assessment During Pregnancy Clinical history Anticoagulation Multiple VTE episodes VTE with high-risk (HR) thrombophilia VTE with acquired thrombophilia Treatment dose LMWH or UFH Idiopathic VTE VTE with pregnancy or oral contraceptive VTE with low risk (LR) thrombophilia Family history of VTE with HR thrombophilia HR thrombophilia Prophylactic LMWH or UFH • At the initial assessment during pregnancy (during the first prenatal care visit), the patient’s clinical history should be reviewed and if the patient has a history of prior VTE events and/or thrombophilias, anticoagulation with low molecular weight or unfractionated heparin should be considered. • For patients with multiple prior events or who have high-risk thrombophilias, treatment dose heparin may be indicated. • For patients with a less concerning history, prophylactic heparin may be indicated. • Lastly, patients with low-risk thrombophilia or a prior provoked event may not require prophylaxis. 1st VTE provoked Family history of VTE with LR thrombophilia LR thrombophilia (including acquired) No treatment Chest, Feb 2012; 141, ACOG Practice Bulletin No 123, 2011

Risk Assessment High-risk thrombophilias are defined as: Factor V Leiden or prothrombin gene mutation homozygous Antithrombin III deficiency Compound heterozygote disorders (FVL and prothrombin) Low-risk thrombophilia Factor V Leiden or prothrombin gene mutation heterozygous Protein C or S deficiency Acquired thrombophilia High-risk thrombophilias are defined as: • Factor V Leiden or prothrombin gene mutation homozygous • Antithrombin III deficiency • Compound heterozygote disorders (factor V Leiden and the prothrombin gene mutation) Low-risk thrombophilias are defined as: • Factor V Leiden or prothrombin gene mutation heterozygotes • Protein C or S deficiency The main acquired thrombophilia is antiphospholipid antibody syndrome. Antiphospholipid antibody syndrome ACOG Practice Bulletin No 123, 2011

Prevalence and Risks of VTE with Thrombophilias Prev in Gen Pop % Lifetime ↑ VTE Risk % of all VTE VTE Risk/Preg (No hx) VTE Risk/Preg (Prior VTE) Low-risk thrombophilias FVL heterozygote 1-15 3-8 40 < 0.3 10 PTG heterozygote 2-5 3 17 < 0.5 >10 Protein C activity (<50%) 0.2-0.4 10-15 14 0.1-0.8 4-17 Protein S free Ag (<55%)** .03-0.1 2 0.1 0-22 High-risk thrombophilias FVL homozygote < 1 1.5 PTG homozygote 0.5 2.8 > 17 FVL/PTG compound 0.01 1-3 4.7 > 20 Antithrombin III def (<60%) 0.02 25-50 1 3-7 • This table demonstrates that patients with a history of thromboembolism and a thrombophilia are at high-risk for an event during pregnancy, particularly in comparison to the nonpregnant state. • The column on the far right demonstrates the probability of an event with a thrombophilia in the setting of a prior event. ** Should not be tested in pregnancy or high-estrogen states. If necessary, levels < 24% in pregnancy in 1 series: Paidas MJ, et al. J Thromb Haemost 2005.

Initial Assessment During Pregnancy Provoked VTE is defined as an event occurring in the setting of a temporary risk factor that increases risk such as: Orthopedic surgery Indwelling line Immobilization Unprovoked VTE occurs in the absence of temporary risk factors. *AN EXCEPTION: VTE provoked by estrogen (OCP, prior pregnancy) should be treated as being at higher risk for recurrence and guidelines for “unprovoked VTE” should be followed for patients with this clinical history See Slide.

Antepartum Hospitalization All patients Mechanical prophylaxis AND All patients: Should be given pharmacologic prophylaxis if risk factors are present (next slide) OR May be given pharmacologic prophylaxis empirically • During antepartum hospitalization, all patients should receive sequential compression devices. • Additionally, pharmacologic prophylaxis in the form of low molecular weight heparin or unfractionated heparin should be added, either empirically OR if patients were receiving prophylaxis as outpatients or have risk factors including medical and obstetrical complications. These recommendations have been adopted primarily from RCOG guidelines

Antepartum Hospitalization Risk-Factor Based Prophylaxis Recommend heparin if at least 1 of the factors below is present: Medical conditions Already receiving LMWH or UFH as outpatient Pre-pregnancy Morbid Obesity (BMI > 40) Any history of VTE Heart disease Lupus Renal disease Sickle cell Major infection Other major medical conditions Prophylactic LMWH or UFH OR 2 or more risk factors below are present: Pregnancy complications Age>40 or <15 years Pre-pregnancy obesity (BMI > 30) Bed rest Any thrombophilia Medical conditions Pregnancy complications The guidance outlined here lists risk factors associated with increased risk for VTE and justify pharmacologic prophylaxis during an antepartum hospitalization. IUGR Preeclampsia Multiple gestation ART RCOG, 2009 Green Top 37a

Delivery Hospitalization Early mobilization Avoid dehydration Chemoprophylaxis based on risk factors All patients Women undergoing cesarean delivery should: Receive sequential compression devices perioperatively and postpartum Receive chemoprophylaxis (LMWH or UFH) either empirically OR based on risk factors During delivery hospitalizations all patients should receive early mobilization, avoid dehydration, and receive chemoprophyalxis based on risk factors. Women undergoing cesarean delivery should receive sequential compression devices perioperatively and postpartum and should receive chemoprophylaxis either empirically or be assessed for risk factors and, if risk factors are present, receive chemoprophylaxis on that basis.

Delivery Hospitalization Recommend heparin if at least 1 of the factors below is present Already receiving heparin as outpatient Pre-pregnancy class 3 obesity (BMI > 40) Any history of VTE Thrombophilia and family history of VTE OR 2 or more risk factors below are present: Prophylactic LMWH or UFH until discharge 2 or more risk factors: Cesarean delivery Hemorrhage (if stable after 12-24 hours) Hysterectomy General anesthesia Postpartum infection Age>40 or <15 years Pre-pregnancy obesity (BMI > 30) Bed rest Any Thrombophilia Medical or pregnancy complications • Risk factors are listed that would justify pharmacologic prophylaxis. • Patients who have one or more major risk factors OR two or more minor risk factors should receive pharmacologic prophylaxis. RCOG, 2009 Green Top 37a

Assessment During Postpartum Discharge Clinical history Anticoagulation Multiple VTE episodes VTE with high-risk (HR) thrombophilia VTE with acquired thrombophilia 6 Weeks Treatment LMWH/UFH Idiopathic VTE VTE with pregnancy or oral contraceptive VTE with low risk (LR) thrombophilia Family history of VTE with HR thrombophilia HR thrombophilia (including acquired) VTE provoked* LR thrombophilia and family history of VTE* 6 Weeks Prophylactic LMWH/UFH • On discharge home, patients should also be assessed. • The management algorithm is the same as for prenatal outpatient management EXCEPT that for postpartum patients with a history of provoked VTE or a family history of VTE with a low-risk thrombophilia, prophylaxis is recommended. * (two changes from initial assessment) LR thrombophilia No treatment Chest, Feb 2012; 141 ACOG Practice Bulletin No 123, 2011

Anticoagulation - LMWH Advantages of LMWH compared to UFH Fewer bleeding episodes Lower risk of heparin induced thrombocytopenia (HIT) Lower incidence of osteoporosis More predictable pharmacokinetics Anti-Xa activity measurement not required for LMWH except for Extremes of body weight Renal impairment LMWH has longer half life than UFH May be an advantage or a disadvantage In terms of a choice of agent, low molecular weight heparin has certain advantages over unfractionated heparin. With low molecular weight heparin, there are fewer bleeding episodes, lower risk of HIT, lower incidence of osteoporosis, and more predictable pharmacokinetics. Anti-Xa activity measurement is not required for LMWH except for extremes of body weight and renal impairment. LMWH has a longer half life than UFH which may be an advantage or disadvantage. Greer et al. Blood. 2005;106(2):401–407 Ni Ainle F et al. Blood Coagul Fibrinolysis. 2008;19 (7):689–692 Nelson-Piercy C et al, Eur J Obstet Gynecol Reprod Biol. 2011, Dec;159(2):293-9.

Contraindications to LMWH Therapy Hemophilia or other known bleeding disorder Active or threatened antenatal bleeding (e.g. placenta previa, placental abruption) based on clinical judgment of balancing risks/benefits (consider holding LMWH/UFH 12-24 hours after cessation of bleeding) Thrombocytopenia (platelet count <75 x109) Recent stroke (hemorrhagic/ischemic) Severe renal disease (GFR <30ml/min) Severe liver disease (prolonged PT) Uncontrolled hypertension (BP >200mmHg systolic or >120mmHg diastolic) Unfractionated heparin should be used if there is a specific contraindication to LMWH Contraindications to LMWH therapy include: • Hemophilia or other known bleeding disorder • Active or threatened antenatal bleeding based on clinical judgment of balancing risks/benefits • Thrombocytopenia • Recent stroke • Severe renal disease • Severe liver disease • Uncontrolled hypertension Unfractionated heparin should be used if there is a specific contraindication to LMWH

Screening for Heparin Induced Thrombocytopenia (HIT) For patients expected to be on either UFH or LMWH for greater than >7 days a complete blood count should be sent to assess for HIT 7-10 days after initiation of therapy A platelet count of <150,000/microL or acute drop to<50% of baseline require further evaluation and immediate consultation with a hematologist or maternal-fetal medicine specialist A preceding diagnosis of gestational thrombocytopenia or idiopathic thrombocytopenic purpura may confound screening for HIT, and consultation with a hematologist or maternal fetal medicine specialist may be required for patients with these conditions Heparin induced thrombocytopenia is a rare but serious complication of heparin therapy HIT is more common with unfractionated heparin than low molecular weight heparin For patients who will undergo an extended course of heparin prophylaxis either inpatient or outpatient (> 7 days), screening for HIT with a CBC 7-10 days after initiation of treatment is recommended A platelet count of <150,000/microL or acute drop to less than <50% of baseline require further evaluation and immediate consultation with a hematologist or maternal-fetal medicine specialist

Prophylaxis and Spontaneous Labor For patients on LMWH prenatally, consideration should be made to switch to UFH at 35-36 weeks gestational age to facilitate administration of regional anesthesia When patients are transitioned from LMWH to UFH, HIT should also be screened for with a CBC 7-10 after UFH is initiated See Slide.

Protocols for Prophylaxis Agent LMWH Enoxaparin   Dalteparin Tinzaparin UFH Unfractionated heparin Weight based Gestational age-based <50kg 20mg daily 2500 units daily 3500 units daily First trimester 5000-7500 units Twice daily 50-90kg 40mg daily 5000 units daily 4500 units daily Second trimester 7500-10000 units 91-130kg 60mg daily* 7500 units daily* 7000 units daily* Third trimester 10000 units 131-170kg 80mg daily* 10000 units daily* 9000 units daily  Postpartum  5000 units twice daily >170kg 0.6mg/kg/day* 75 units/kg/day • For prophylaxis, low molecular weight heparin dosing during pregnancy differs based on which agent is being used and the patient’s weight. • For unfractionated heparin, dosing depends on the trimester. • For antepartum patients it is reasonable to administer a dose of 5000 units UFH twice daily during hospitalization for prophylaxis to facilitate regional anesthesia. Hospitalized antepartum patients may receive 5000 units UFH twice daily for prophylaxis to facilitate regional anesthesia *=may be given in two divided doses Adapted from ACOG Practice Bulletin 123, ACCP Recommendations , RCOG Green Top Guideline 37a

Protocols for Therapeutic Dosing LMWH Enoxaparin   Dalteparin Tinzaparin Unfractionated heparin Warfarin (postpartum) Dosing: Antepartum or Postpartum 1mg/kg twice daily 200 units/kg/day 175 units/kg/day 10000 units or more twice daily adjusted to mid interval target aPTT (1.5-2.5) INR 2.0-3.0 (postpartum only) • Protocols for therapeutic dosing are based on patient weight for LMWH and achieving a therapeutic PTT for heparin. • Warfarin is not used during pregnancy except in extremely rare conditions such as mechanical heart valves. • Warfarin postpartum is dosed based on INR testing. Adapted from ACOG Practice Bulletin 123

Timing of Neuroaxial Anesthesia Antepartum/Intrapartum UFH prophylaxis (≤10,000IU/day) No contraindications to timing of heparin dose and performance of neuraxial blockade UFH therapeutic Wait 6 hours post last dose prior to neuraxial blockade LMWH prophylaxis Wait 12 hours post last dose prior to neuraxial blockade LMWH therapeutic Wait 24 hours post last dose prior to neuraxial blockade Postpartum  Wait ≥1 hour after epidural catheter removal or spinal needle placement Wait ≥4 hours after epidural catheter removal or spinal needle placement Avoid therapeutic dosing with epidural catheter in situ. Wait at least 24 hours after catheter removal or spinal needle This table demonstrates recommendations for timing of neuroaxial anesthesia in relation to pharmacological anticoagulation. • Twice daily UFH at a dose of 5000 units is typically not a contraindication to neuraxial anesthesia • For therapeutic UFH neuraxial anesthesia should be deferred 6 hours after the last dose • For prophylactic and therapeutic LMWH neuraxial anesthesia should be deferred 12 and 24 hours after the last dose respectively • Postpartum UFH may be given 1 hour after spinal or epidural catheter removal • Postpartum LMWH may be given 4 hours after spinal or epidural catheter removal • Therapeutic LMWH may be given 24 hours after spinal or epidural catheter removal Sources: FDA Drug Safety Communication Nov, 2013; NYP protocol

Post-Cesarean Prophylaxis Unfractionated heparin (UFH) The patient should receive the first dose of UFH on meeting criteria for PACU discharge, but no sooner than one hour after epidural catheter removal Standard order 5000 units SC every 12 hours If an epidural catheter remains in situ for pain control, it should not be removed until 3 hours after last dose of UFH Intraoperative UFH (infrequent) should be given no sooner than 30 minutes after spinal or epidural See Slide. NYP protocol

Post-Cesarean Prophylaxis Low-molecular-weight heparin (LMWH) The patient should receive the first dose of LMWH no sooner than 6 hours postoperatively regardless of anesthesia technique If an epidural catheter remains in situ for pain control, it should not be removed until 12 hours after last dose of LMWH If the epidural catheter is to be removed prior to a dose of LMWH, the LMWH may not be given until 4 hours after removal See Slide. Sources: FDA Drug Safety Communication Nov, 2013; NYP protocol

Therapeutic Postpartum Prophylaxis For patients who have therapeutic LMWH postpartum anticoagulation planned: LMWH should be deferred until at least 24 hours after spinal needle placement or epidural catheter removal Prophylactic UFH dosing should be considered during the 24 hours postpartum after regional anesthesia for these patients For patients with major risk factors for hemorrhage precluding therapeutic LMWH (recent postpartum hemorrhage, wound hematoma, coagulopathy) prophylactic UFH and/or SCDs should be considered See Slide.

Conclusion All patients require VTE risk assessment at multiple time points in pregnancy and postpartum All patients undergoing cesarean delivery require mechanical prophylaxis, early ambulation, and adequate hydration Women with additional risk factors for VTE after delivery will benefit from pharmacologic prophylaxis Empiric pharmacologic prophylaxis for all women undergoing cesarean delivery and for all antepartum hospital admissions is a reasonable clinical strategy Key papers include major society guidelines, an overview of the role of VTE in maternal morbidity and mortality, and evidence that VTE prophylaxis is suboptimal in the United States.