1. Venous Thromboembolism: Risk Assessment and Prophylaxis

2. 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
• Venous thromboembolism or VTE for short is a leading cause of maternal mortality and severe morbidity
• Maternal death from VTE is amenable to prevention and prophylaxis has been identified as the most readily implementable means of systemically reducing the maternal death rate
• Use of 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

3. 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
The key elements that will be presented include the following:
• Risk assessment tools for VTE that assess patient risk for events during key points in pregnancy
• Protocols for antenatal and postpartum thromboembolism prophylaxis
• Suggested dosing recommendations for medications for prophylaxis
• Anesthesia recommendations for placement of regional anesthesia in patients receiving anticoagulation medications
• Key references including international guidelines and key papers

4. 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
A premise underlying improve care quality is that all patients should be assessed for VTE risk multiple times in pregnancy.
All patients should be assessed for VTE risk multiple times in pregnancy including during:
• Presentation for prenatal care
• Hospitalization for an antepartum indication
• The postpartum period of a delivery hospitalization
• On discharge home from a delivery hospitalization
• Prophylaxis can be based on risk factors or can be empiric

5. 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 Joint Commission Specifications Manual for National Hospital Inpatient Safety
• Thromboembolism prophylaxis may be an important measure of health care quality
• Thromboembolism prophylaxis has been adopted as a Joint Commission quality measure
• 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 or within a day of surgery

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

7. 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
• Risk assessment tools were based on recommendations from major society guidelines
• An iterative process determined the final recommendations
• Prenatal outpatient and postpartum discharge thromboprophylaxis are based primarily on Chest and ACOG recommendations
• Inpatient prophylaxis is based primarily on RCOG recommendations
• Pharmacologic prophylaxis may be with unfractionated heparin or low-molecular weight heparin

8. 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 prophylais.
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

9. Risk Assessment High-risk thrombophilia Low-risk thrombophilia
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 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

10. 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%)
10-15 14
4-17
Protein S free Ag (<55%)** 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 slide 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 right demonstrates the probability of an event with a thrombophilia in the setting of a prior event.
• Patients with high risk thrombophilias are most likely to have an event.usually beginning at fetal viability at about 24 weeks gestation.
** 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.

11. 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 (including acquired)
Prophylactic
LMWH or UFH
This increased risk is the rationale for providing prophylaxis to high risk patients as outpatients during prenatal care, with treatment dose heparin for patients with the most concerning clinical risk factors.
1st VTE provoked
Family history of VTE with LR thrombophilia
LR thrombophilia
No treatment
Chest, Feb 2012; 141, ACOG Practice Bulletin No 123, 2011

12. 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
In the context of risk assessment 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 to this definition is that VTE provoked by estrogen should be treated as being at higher risk for recurrence and guidelines for unprovoked VTE should be followed for patients with this clinical history

13. 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 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 based on risk factors

14. 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
• 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, 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
IUGR
Preeclampsia
Multiple gestation
ART
RCOG, 2009 Green Top 37a

15. 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 based on risk factors

16. 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
Hysterectomy
General anesthesia
Postpartum infection
Age>40 or <15 years
Pre-pregnancy obesity (BMI > 30)
Bed rest
Any Thrombophilia
Medical or pregnancy complications
• On this slide, risk factors are listed that would justify pharmacologic prophylaxis
• Patients who have one or more major risk factor or two or more minor risk factors should receive pharmacologic prophylaxis
RCOG, 2009 Green Top 37a

17. 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

18. 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 excpet 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.

19. 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
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

20. 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
For patients on LMWH prenatally, consideration should be made to switch to UFH at weeks gestational age to facilitate administration of regional anesthesia

21. Prophylaxis and Spontaneous Labor
For patients on LMWH prenatally, consideration should be made to switch to UFH at 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
For patients on LMWH prenatally, consideration should be made to switch to UFH at weeks gestational age to facilitate administration of regional anesthesia

22. 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
units
Twice daily
50-90kg
40mg daily
5000 units daily
4500 units daily
Second trimester
units
91-130kg
60mg daily*
7500 units daily*
7000 units daily*
Third trimester
10000 units kg
80mg daily*
10000 units daily*
9000 units 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 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 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

23. 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 ( )
INR
(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

24. Timing of Neuroaxial Anesthesia
• This slide 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

25. 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
• If a patient is receiving unfractionated heparin for postcesarean prophylaxis, the patient should receive the first dose on meeting criteria for PACU discharge, but no sooner than one hour after epidural catheter removal.
• A standard order is 5000 units subq every 12 hours.
• If an epidural catheter remains in situ for pain control, it should not be removed until 3 hours after the last dose of UFH.
• Intraoperiative heparin (which is given infrequently) should be given no sooner than 30 minutes after spinal or epidural
NYP protocol

26. 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
• When low molecular weight heparin is given for post-cesarean prophylaxis, the patient should receive the first dose of LMWH no sooner
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 dose of LMWH.
• If the epidural catheter is to be removed prior to a dose of LMWH, the LMWH may not be given until four hours after removal
Sources: FDA Drug Safety Communication Nov, 2013; NYP protocol

27. 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
For patients who have therapeutic LMHW postpartum anticoagulation planned:
• LMWH should be deferred until at least 24 hours after spinal needle placement or epidural catheter removal
• Prophylactic UFH should be considered during the 24 hours postpartum after regional anesthesia
• For patients with major risk factors for hemorrhage precluding therapeutic LMWH prophylactic UFH and/or SCDs should be considered

28. 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
• In 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