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460 Anticoagulation Therapy
https://t.me/med1917
TABLE 19-6: UFH and LMWH Regimens and Associated Doses
as Defined by ACCP and ACOG
ACCP ACOG
Mini-dose
prophylactic UFH
Prophylactic LMWH Dalteparin 5,000 units sub-Q q
Prophylactic UFH UFH 5,000–10,000 units sub-Q
Intermediate dose
LMWH
Adjusted dose
LMWH
Adjusted dose UFH
Postpartum
anticoagulation
24 hr
Enoxaparin 40 mg sub-Q q 24 hr
Tinzaparin 4,500 units sub-Q q
24 hr
(At extremes of body weight,
modification of dose may be
required.)
Dalteparin 5,000 units sub-Q q
12 hr
Enoxaparin 40 mg sub-Q q 12 hr
Weight-adjusted, full treatment
doses of LMWH, given once or
twice daily
Dalteparin 200 units/kg daily
Tinzaparin 175 units/kg daily
Dalteparin 100 units/kg q 12 hr
Enoxaparin 1 mg/kg q 12 hr
UFH sub-Q q 12 hr in doses
adjusted to target a mid-interval
aPTT into the therapeutic range
VKAs for 6 weeks with a target
INR of 2–3, with initial UFH
or
LMWH overlap until the INR is >2,
or prophylactic or intermediatedose LMWH for 6 weeks
11,33
5,000 units sub-Q q 12 hr
Dalteparin 5,000 units sub-Q daily
Enoxaparin 40 mg sub-Q daily
Tinzaparin 4,500 units sub-Q daily
(At extremes of body weight,
modification of dose may be
required.)
q 12 hr
UFH 5,000–7,500 units q 12 hr
first trimester
UFH 7,500–10,0000 units sub-Q q
12 hr second trimester
UFH 10,000 units sub-Q q 12
hr third trimester unless aPTT
elevated
Not defined
Enoxaparin 1 mg/kg q 12 hr
Dalteparin 200 units/kg daily
Tinzaparin 175 units/kg daily
Dalteparin 100 units/kg q 12 hr
Target anti-Xa 0.6–1 units/ml mL
for twice daily regimen; slightly
higher doses may be needed for a
once-daily regimen
10,000 units or more sub-Q q
12 hr in doses adjusted to target
aPTT 1.5–2.5 x control 6 hr after
injection
Prophylactic LMWH/UFH 4–6
weeks or VKA 4–6 weeks with
target INR 2–3, with UFH/LMWH
overlap until INR 2 or more for
2 days
(continued)
PREGNANCY 461
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TABLE 19-6: (Continued)
ACCP ACOG
Surveillance
ACCP: American College of Chest Physicians, ACOG: American College of Obstetrics and
Gynecology, aPTT: activated partial thromboplastin time, hr: hours, INR: international normalized
ratio, LMWH: low molecular weight heparin, sub-Q: subcutaneous, UFH: unfractionated heparin,
VKA: vitamin K antagonist, VTE: venous thromboembolism, x: times
Source:
Adapted with permission from Bates SM, Greer IA, Pabinger I, et al. Venous
thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. American College
of Chest Physicians Evidence-based Clinical Practice Guidelines (8th ed).
Suppl):844S-886S.
Clinical vigilance refers to
patient and physician alertness
to signs and symptoms of VTE
and awareness of the need for
timely and appropriate objective
investigation.
Clinical vigilance and appropriate
objective investigation of women
with symptoms suspicious of VTE
may be needed.
Chest.
2008;133(6
Risk of VTE in Pregnant Women with Thrombophilia
A strong association exists between inherited thrombophilia and venous
thromboembolism, making detection of these mutations a part of prevention strategies. The risks for VTE associated with different thrombophilia are
described in Table 19-7. However, it is not clear whether inherited thrombo-
philia lead to such adverse pregnancy outcomes as fetal loss, preeclampsia,
intrauterine growth restriction, and placental abruption.
Prevention of VTE During Pregnancy
•
ACOG provides recommendations for when to screen pregnant women for
thrombophilia (Table 19-8).
•
Low-risk thrombophilia are defined as Factor V Leiden heterozygous; prothrombin
G20210A heterozygous; protein C or protein S deficiency.
•
High-risk thrombophilia includes antithrombin deficiency; double heterozygous
for prothrombin G20210A mutation and factor V Leiden; factor V Leiden homozy
gous or prothrombin G20210A mutation homozygous.
•
Both ACCP and ACOG provide slightly different recommendations for VTE
prevention in patients with no prior history of VTE (Table 19-9). These recom
mendations consider whether or not the patient has a family history of VTE.
Separate recommendations also exist that consider whether the patient has had
a previous VTE (Table 19-10).
-
-
462 Anticoagulation Therapy
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TABLE 19-7: Risk of VTE Associated with Different
Thrombophilias
Thrombophilia Prevalence
Antithrombin III activity
(<60%)
Factor V Leiden
heterozygote
Factor V Leiden homozygote <1 4 17 2
Factor V Leiden/Prothrombin
double heterozygote
Protein C activity (<50%) 0.2–0.4 0.1–0.8 4–17 14
Protein S free antigen
(<55%)
Prothrombin gene
heterozygote
Prothrombin gene
homozygote
VTE: venous thromboembolism
11
(%)
0.02 3−7 40 1
1–15 0.5–1.2 10 40
0.01 4−5 >20 1–3
0.03–0.13 0.1 0–22 3
2–5 <0.5 >10 17
<1 2-–4 >17 0.5
VTE Risk per
Pregnancy
(No History)
(%)
VTE Risk per
Pregnancy
(Previous VTE)
(%)
% of all VTE
TABLE 19-8: Screening for Thrombophilia in Pregnancy
Screening for thrombophilia in pregnancy recommended:
• Personal history of VTE associated with a nonrecurrent RF (fracture, surgery, immobilization)
Recurrence risk among untreated pregnant women with such a history and a
thrombophilia was 16% (OR 6.5; 95% CI 0.8–56.3).
• First degree relative with history of high-risk thrombophilia.
In other situations, thrombophilia testing not routinely recommended:
• Testing for inherited thrombophilia in women who have experienced recurrent fetal loss
or placental abruption is not recommended because it is unclear if AC therapy reduces
recurrence (Level B).
• Insufficient evidence to either screen for or treat women with inherited thrombophilia and
obstetric histories that include complications such as IUGR or preeclampsia (Level B).
AC: anticoagulation, IUGR: intrauterine growth restriction, RF: risk factor, VTE: venous
thromboembolism
11
PREGNANCY 463
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TABLE 19-9: ACCP and ACOG Recommendations for VTE
Prevention in Patients with No Prior History of VTE
No Prior VTE, No Family
History for VTE
Homozygous factor V Leiden
or Prothrombin mutation
Antithrombin deficiency,
double heterozygous
Prothrombin G2010A
mutation, and factor V Leiden
mutation
All other thrombophilia AP and PP: Clinical vigilance
No Prior VTE + Family History for VTE
Homozygous factor V Leiden
or prothrombin mutation and
+ family history for VTE
Antithrombin deficiency,
double heterozygous
prothrombin G2010A and
factor V Leiden and + family
history for VTE
All other thrombophilia who
have + family history for VTE
a
Refer to Table 19-2 for corresponding dosing regimens.
AC: anticoagulation, ACCP: American College of Chest Physicians, ACOG: American College
of Obstetrics and Gynecology, AP: antepartum, INR: international normalized ratio, LMWH: low
molecular weight heparin, PP: postpartum, tx: therapy, UFH: unfractionated heparin, VKA: vitamin
K antagonist, VTE: venous thromboembolism
Source:
Adapted from Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism,
thrombophilia, antithrombotic therapy, and pregnancy. American College of Chest Physicians
Evidence-based Clinical Practice Guidelines (8th ed).
ACCP 2012 ACOG 2013
AP: Clinical vigilance
PP: Prophylactic or
intermediate dose LMWH or
VKA INR 2–3 for 6 weeks over
routine care
AP: Clinical vigilance over
pharmacologic prophylaxis
PP: Clinical vigilance over
pharmacologic prophylaxis
over pharmacologic
prophylaxis
AP: Prophylactic or
intermediate dose LMWH
PP: Prophylactic or
intermediate dose LMWH or
VKA INR 2–3 for 6 weeks over
no prophylaxis
AP: Clinical vigilance
PP: Prophylactic or
intermediate dose LMWH or,
in women who are not protein
C or S deficient, VKA INR 2–3
over routine care
AP: Clinical vigilance
PP: Prophylactic or
intermediate dose LMWH or,
in women who are not protein
C or S deficient, VKA INR 2–3
over routine care
Chest.
From Bulletin #138
High-risk thrombophilia
AP: Surveillance without AC
tx, or prophylactic LMWH/
UFH
High-risk thrombophilia
AP: Surveillance without AC
tx or prophylactic LMWH/UFH
PP: AC tx
Low-risk thrombophilia
AP: Surveillance without AC
PP: Surveillance without AC
or PP AC if + risk factors
High-risk thrombophilia with
1 prior VTE or 1st degree
relative
AP: Prophylactic, intermediate
dose or adjusted dose
LMWH/UFH
PP: PP AC or intermediate or
adjusted dose LMWH/UFH
6 weeks
High-risk thrombophilia with
1 prior VTE or 1st degree
relative
AP: Prophylactic, intermediate
dose, or adjusted dose
LMWH/UFH
PP: PP AC or intermediate or
adjusted dose LMWH/UFH
6 weeks
Low-risk thrombophilia
AP: Surveillance without
AC tx
PP: PP AC or intermediate
dose LMWH/UFH
2008;133(6 Suppl):844S-886S.
11,33,a
464 Anticoagulation Therapy
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TABLE 19-10: ACCP and ACOG Recommendations for VTE
Prevention in Patients with Previous VTE
VTE Prophylaxis: No
Thrombophilia, Prior VTE
Low risk of recurrent VTE
(single episode of VTE
associated with transient
risk factor not related to
pregnancy or estrogen)
Moderate/high risk of
recurrent VTE (single
unprovoked VTE, pregnancyor estrogen-related VTE, or
multiple prior unprovoked
VTE not receiving long-term
AC)
On long-term VKA prior to
pregnancy
ACCP 2012 ACOG 2013 (From Bulletin
AP: Clinical vigilance over AP
prophylaxis
PP: Prophylactic or
intermediate dose LMWH
or VKA INR 2–3 over no
prophylaxis
AP: Prophylactic or
intermediate-dose LMWH
over clinical vigilance or
routine care
PP: Prophylactic or
intermediate dose LMWH
or VKA INR 2–3 over no
prophylaxis
AP: Adjusted-dose LMWH or
75% of a therapeutic dose of
LMWH
PP: Resume long-term AC
over prophylactic dose
LMWH
11,33,a
#138)
AP: Surveillance without AC
Pregnancy related:
AP: Prophylactic LMWH or
UFH
PP: PP AC tx
Idiopathic VTE:
AP: Prophylactic LMWH/UFH
PP: PP AC
Multiple VTE not on long
term AC:
AP: Prophylactic or
therapeutic LMWH/UFH
PP: AC
AP: Therapeutic dose LMWH
or UFH
PP: Resume long-term AC
VTE Prophylaxis:
Thrombophilia and Prior
VTE
Low-risk thrombophilia (factor
V Leiden heterozygous,
prothrombin G0210A
heterozygous, protein C or
protein S deficiency) with
single previous VTE (not
receiving long-term AC)
High-risk thrombophilia
(antithrombin deficiency,
double heterozygous for
prothrombin G2010A
mutation and factor V Leiden,
Factor V Leiden homozygous,
or Prothrombin G20210A
mutation homozygous) with
a single previous episode of
VTE (not receiving long-term
AC)
ACCP 2012 ACOG 2013 (From Bulletin
#138)
AP: Prophylactic or
intermediate-dose LMWH/
UFH or surveillance without
AC
PP: PP AC or intermediate
dose LMWH/UFH
AP: Prophylactic,
intermediate-dose, or
adjusted dose LMWH/UFH
regimen
PP: PP AC or intermediate or
adjusted dose LMWH/UFH
for 6 weeks (therapy level
should be at least as high as
AP treatment)
(continued)
TABLE 19-10: (Continued)
https://t.me/med1917
VTE Prophylaxis:
Thrombophilia and Prior
VTE
ACCP 2012 ACOG 2013 (From Bulletin
PREGNANCY 465
#138)
Thrombophilia or no
thrombophilia with 2 or
more episodes of VTE (not
receiving long-term AC)
Thrombophilia or no
thrombophilia with 2 or more
episodes of VTE (receiving
long-term AC)
a
Refer to Table 19-6 for corresponding dosing regimens.
AC: anticoagulation, ACCP: American College of Chest Physicians, ACOG: American College
of Obstetrics and Gynecology, AP: antepartum, INR: international normalized ratio, LMWH: low
molecular weight heparin, PP: postpartum, tx: therapy, UFH: unfractionated heparin, VKA: vitamin
K antagonist, VTE: venous thromboembolism
Source:
Adapted from Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism,
thrombophilia, antithrombotic therapy, and pregnancy. American College of Chest Physicians
Evidence-based Clinical Practice Guidelines (8th ed).
Chest.
AP: Prophylactic or
therapeutic dose LMWH or
UFH
PP: PP AC or therapeutic
dose LMWH/UFH for 6 weeks
AP: Therapeutic dose LMWH
or UFH
PP: Resumption of long-term
AC tx
2008;133(suppl 6):844S-886S.
• Multiple anticoagulants may be acceptable
for use during pregnancy and the postpartum
period. Drug selection decision depends on
efficacy, safety to the mother and the fetus (e.g.,
bleeding risk, risk during lactation), and patient
preferences. Strategies may differ in the United
States and Europe.
•
For dosing and monitoring of LMWH/UFH for
VTE prophylaxis:
LMWH recommended over UFH for the
11,33
prevention and treatment of VTE (ACCP
Grade 2C).
Higher doses of LMWH may be needed to
achieve target prophylactic anti-factor Xa
levels, especially in obese patients (i.e.,
enoxaparin 40 mg twice daily [BID],
dalteparin 5,000 units BID).
Monitoring of anti-factor Xa levels in
this setting is controversial; if performed,
checking every 1–3 months is reasonable.
466 Anticoagulation Therapy
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Target anti-factor Xa levels of 0.1–0.3
International Units/mL have been
recommended by some, while others
recommend 0.2–0.6 International Units/mL.
No comparative studies have been conducted.
•
Monitoring aPTT levels is generally not
recommended for prophylactic dosing of UFH.
ACCP Considerations of Cesarean Section
ACCP has compiled a list of major and minor risk factors used to identify
women at increased risk of VTE after a cesarean section (Table 19-11). The
TABLE 19-11: Risk Factors for VTE with a Baseline Risk of
Postpartum VTE of >3%
Major risk factors
(OR >6)
Minor risk factors (OR
>6 when combined)
• Immobility (strict bedrest for ≥1 week in the antepartum period)
Postpartum hemorrhage ≥1,000 mL with surgery
•
•
Previous VTE
Preeclampsia with fetal growth restriction
•
•
Thrombophilia
•
Medical conditions
• Blood transfusion
• Postpartum infection
• BMI >30 kg/m
• Multiple pregnancy
• Postpartum hemorrhage >1 Liter
• Smoking > 10 cigarettes/day
• Fetal growth restriction (gestational age + sex-adjusted birth
• Thrombophilia
• Preeclampsia
33
Antithrombin deficiency
Factor V Leiden (homozygous or heterozygous)
Prothrombin G20210A (homozygous or heterozygous)
Systemic lupus erythematosus
Heart disease
Sickle cell disease
2
weight <25th percentile)
Protein C deficiency
Protein S deficiency
OR: odds ratio, VTE: venous thromboembolism
Source:
Adapted from Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism,
thrombophilia, antithrombotic therapy, and pregnancy. American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines (8th ed).
Chest.
2008;133(6 Suppl):844S-886S.
PREGNANCY 467
https://t.me/med1917
presence of one major or two or more minor risk factors will indicate whether
patients qualify for thrombosis prophylaxis (Table 19-12). When major
risk factors continue in the puerperium, consideration should be given to
extending prophylaxis for the 6 weeks during which pregnancy-associated
prothrombotic changes may persist.
Prevention of Arterial Events During Pregnancy
Prevention of arterial events during pregnancy includes anticoagulation
management of patients with mechanical heart valves, as well as patients
with atrial fibrillation.
TABLE 19-12: ACCP Considerations of Cesarean Section
Without additional thrombosis risk factors:
• Recommend against the use of thrombosis prophylaxis other than early mobilization
(Grade 1B).
Increased risk of VTE because of 1 major or ≥2 minor risk factors:
• Suggest pharmacologic prophylaxis (prophylactic LMWH) or mechanical prophylaxis
(ES or IPC) in those with contraindications to AC while in hospital after delivery over no
prophylaxis (Grade 2B).
Very high risk for VTE and multiple additional risk factors for TE that persist in the puerperium:
• Suggest prophylactic LMWH be combined with ES and/or IPC over LMWH alone (Grade
2C).
Selected high-risk patients with significant risk factors that persist following delivery:
• Suggest extended prophylaxis (up to 6 weeks after delivery) following discharge from the
hospital (Grade 2C).
ACCP: American College of Chest Physicians, ES: elastic stockings, IPC: intermittent pneumatic
compression, LMWH: low molecular weight heparin, TE: thromboembolism, VTE: venous
thromboembolism
33
468 Anticoagulation Therapy
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TABLE 19-13: Anticoagulation with Mechanical Heart Valves
During Pregnancy
ACCP Recommend one of the following AC regimens in preference to no anticoagulation
AHA/ACC
2014
(All Grade 1A):
•
Adjusted-dose BID LMWH throughout pregnancy. Suggest that doses be
• Adjusted-dose UFH throughout pregnancy administered sub-Q every 12
• UFH or LMWH (as above) until the 13th week, with substitution by VKA until
In women at very high risk of TE with concerns about efficacy and safety of LMWH or
UFH (older generation prosthesis in mitral position or hx of TE):
•
Suggest VKA throughout pregnancy with replacement by UFH or LMWH
Pregnant women with prosthetic valves at high risk of TE:
Suggest addition of low dose ASA 75–100 mg/day (Grade 2C).
•
Therapeutic anticoagulation with frequent monitoring is recommended for all
pregnant patients with a mechanical prosthesis (Grade 1B):
First trimester:
•
Warfarin if dose <5 mg/day (Grade IIa B).
•
Dose adjusted LMWH at least two x per day (with a target anti-factor Xa level
• Dose-adjusted LMWH at least two x per day (with a target anti-Xa level of
• Dose-adjusted continuous infusion IV UFH (with an aPTT at least two x
• Dose-adjusted continuous infusion IV UFH (with aPTT at least two x control) if
Second and third trimesters:
• Warfarin to goal INR (Grade 1B).
• Discontinuation of warfarin with initiation of IV UFH (with an activated aPTT
• Low-dose aspirin in addition to anticoagulation with mechanical prosthesis or
12,33
adjusted to achieve the manufacturer’s peak anti-factor Xa LMWH 4 hr post
sub-Q injection or
hr in doses adjusted to keep the mid-interval aPTT at least twice control or
attain an anti-factor Xa heparin level of 0.35−0.70 units/mL or
close to delivery when UFH or LMWH is resumed.
close to delivery rather than one of the other regimens (Grade 2C).
of 0.8–1.2 units/mL, 4–6 hr postdose) if warfarin dose is >5 mg/day (Grade
IIa B).
0.8–1.2 units/mL, 4–6 hr post-dose) if the dose of warfarin is ≤5 mg/day to
achieve a therapeutic INR (Grade IIb B).
control) if the dose of warfarin is >5 mg/day to achieve a therapeutic INR
(Grade IIa B).
the dose of warfarin is ≤5 mg/day to achieve a therapeutic INR (Grade IIb B).
>2 x control) is recommended before planned vaginal delivery (Grade IC).
bioprosthesis (Grade 1C).
LMWH should not be administered unless anti-factor Xa levels are monitored 4–6 hr
after administration (Grade III B).
AC: anticoagulation, ACC: American College of Cardiology, ACCP: American College of Chest
Physicians, AHA: American Heart Association, ASA: acetylsalicylic acid, aPTT: activated partial
thromboplastin time, hr: hours, hx: history, INR: international normalized ratio, IV: intravenous,
LMWH: low molecular weight heparin, sub-Q: subcutaneous, TE: thromboembolism, UFH:
unfractionated heparin, VKA: vitamin K antagonist, x: times
Source:
Adapted from Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism,
thrombophilia, antithrombotic therapy, and pregnancy. American College of Chest Physicians
Evidence-based Clinical Practice Guidelines (8th ed).
Chest.
2008;133(6 Suppl):844S-886S.
PREGNANCY 469
https://t.me/med1917
For dosing and monitoring of UFH and LMWH for
mechanical heart valves:
In pregnancy, particularly in the third trimester,
•
an increase in heparin-binding proteins—
combined with elevated factor VIII levels—can
attenuate the activated partial thromboplastin
time (aPTT) response leading to heparin
resistance; consider plasma heparin levels if
there is difficulty achieving a therapeutic aPTT
response despite infusing 30,000–35,000 units
intravenously per 24 hours.
•
For subcutaneous (sub-Q) UFH dosing to achieve
therapeutic aPTT: Initiate doses starting at
18 units/kg × weight (in kg) × 24 hr × 1.2,
divided every 12 hours. (A correction factor of
1.2 can be applied to account for the 10−20%
loss of bioavailability with sub-Q absorption—
see Chapter 3 for more information on dose
adjustments.)
For example, an 80-kg patient would start at
20,000 units sub-Q every 12 hours.
Check aPTT levels 6 hours after dose is
given.
Use 20,000 units/mL single dose,
preservative-free heparin vials.
Increase or decrease dose by 2,000–5,000 units
with follow-up aPTT levels every 3 days.
• The range for peak anti-factor Xa levels in
women with mechanical heart valves using
LMWH is controversial. Current ACCP
recommendations do not include a target antifactor Xa level, while ACC/AHA recommends
a target peak anti-factor Xa levels (4–6 hours
post-dose) of 0.8–1.2 International Units/mL.
Others have suggested 12-hour trough levels
>0.5 International Units/mL. Clinical judgment
should include the type and location of the valve,
previous history of thromboembolism (TE), and
other risk factors for TE and bleeding.
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