Thromboembolic Disorders
BS. Nguyễn Hồng Anh
During the past century, the requency o venous thromboembolism (VE) uring the puerperium ecrease remarkably
as early ambulation became routine practice. Despite this an
other avances in prevention an treatment, thromboembolism
remains a leaing cause o maternal morbiity an mortality
(Abe, 2019). Trombotic pulmonary embolism accounte or
almost 10 percent o pregnancy-relate eaths in the Unite
States between 2011 an 2015 (Creanga, 2017; Petersen, 2019).
Te absolute incience o VE uring pregnancy is low—1
or 2 cases per 1000 pregnancies. However, the risk is approximately ve times higher than that among women who are not
pregnant (Greer, 2015). Approximately equal numbers o cases
are ientie antepartum an in the puerperium. But eep-vein
thrombosis alone is more requent antepartum, an pulmonary embolism is more common postpartum. During the rst
6 weeks o the puerperium, the estimate incience o a thromboembolic complication is 22 events per 100,000 eliveries.
Although still elevate, the risk alls to approximately 3 cases
per 100,000 eliveries uring the secon 6-week postpartum
perio (Kamei, 2014). As many as 2 percent o these women
have postthrombotic synrome (Govinappagari, 2020).
PATHOPHYSIOLOGY
Ruol Virchow (1856) postulate that stasis, local trauma to
the vessel wall, an hypercoagulability preispose to venous
thrombosis. During pregnancy, the risk or each o these rises.
Compression o the pelvic veins an inerior vena cava by the
enlarging uterus reners the lower extremity venous system particularly vulnerable to stasis. Marik an Plante (2008) cite a
50-percent reuction in venous ow velocity in the legs that
lasts rom the early thir trimester until 6 weeks postpartum.
Tis stasis is the most constant preisposing risk actor or
venous thrombosis. Venous stasis, elivery, preeclampsia, an
sepsis contribute to enothelial cell injury. Last, as liste in the
Appenix (p. 1228), the synthesis o most clotting actors is
markely enhance uring pregnancy an avors coagulation.
Risk actors or eveloping VE uring pregnancy are
shown in Table 55-1. Te most important o these is a personal history o thrombosis. Specically, 15 to 25 percent o
all VE cases uring pregnancy are recurrent events (American
College o Obstetricians an Gynecologists, 2020b). Another
important iniviual risk actor is a genetically etermine
thrombophilia. An estimate 20 to 50 percent o women who
evelop a venous thrombosis uring pregnancy or postpartum
have an ientiable unerlying procoagulant genetic isorer
(American College o Obstetricians an Gynecologists, 2020a).
Calculate risks or thromboembolism are approximately
ouble in women with multietal gestation, anemia, hyperemesis, hemorrhage, cesarean elivery, obesity, preeclampsia,
an postpartum inection (Walman, 2013). Scheres an
TABLE 55-1. Some Risk Factors Associated with an
Increased Risk for VTE
Obstetrical General
Cesarean delivery
Cesarean hysterectomy
Diabetes mellitus
Hemorrhage and anemia
Hyperemesis
Immobility—prolonged
bed rest
Multifetal gestation
Multiparity
Preeclampsia
Puerperal infection
Stillbirth
Age 35 years or older
Anatomical anomalya
Antiphospholipid antibodies
Connective tissue disease
Dehydration
Hormonal contraceptives
Hospitalization
Immobility
Infection and inflammatory
disease
Inflammatory bowel disease
Malignancy
Nephrotic syndrome
Obesity
Orthopedic procedures
Paraplegia
Prior VTE
Sickle-cell disease
Smoking
Surgery
Thrombophilia
aIncludes May-Thurner syndrome (iliac vein compression
syndrome).
VTE = venous thromboembolism.
absence o well-recognize risk actors. O greatest signicance
is a amily history o suen eath ue to pulmonary embolism
or a history o multiple amily members requiring long-term
anticoagulation therapy because o recurrent thrombosis (Connors, 2017).
Antithrombin Deficiency
Synthesize in the liver, antithrombin is one o the most important inhibitors o thrombin an inactivates thrombin an actor
Xa (Rhéaume, 2016). Notably, the rate o antithrombin interaction with its target is accelerate over 1000–o1 by heparin.
Antithrombin eciency may result rom hunres o ierent
mutations that are almost always autosomal ominant. ype I
eciency results rom reuce synthesis o biologically normal
antithrombin, an type II eciency is characterize by normal
levels o antithrombin with reuce unctional activity.
Homozygous antithrombin eciency is lethal. Heterozygous
eciency aects approximately 1 in 2500 iniviuals. It is the
most thrombogenic o the heritable coagulopathies. Te risk or
thrombosis correlates with the egree o eciency. Antithrombin eciency is associate with a 25- to 50-ol higher relative
risk o VE in the general population an a sixol increase
risk o thromboembolic complications uring pregnancy (Ilonczai, 2015). As shown in able 55-2, those aecte have an
inorinately high risk o VE uring pregnancy.
Sabaell an associates (2010) stuie the outcomes o 18
pregnancies complicate by antithrombin eciency. welve o
these women were treate with therapeutic oses o low-molecular-weight heparin (LMWH). Tree o the untreate patients
suere a thromboembolic episoe compare with none in the
treate group. Untreate women also ha a 50-percent risk o
stillbirth an etal-growth restriction. By comparison, none o
the treate women ha a stillbirth, but a ourth evelope etalgrowth restriction. Abbattista an coworkers (2020) reporte a
7-percent risk o VE or women treate with LMWH uring
pregnancy an a 12-percent risk or those not treate. Similar
results were reporte by Ilonczai an colleagues (2015). Last,
Garcia-Botella an associates (2016) escribe a mesenteric vein
thrombosis in a pregnant woman with antithrombin eciency.
Given such risk, aecte women are manage uring pregnancy with anticoagulation regarless o whether they have
ha a prior thrombosis (Abbattista, 2020; Bates, 2018). When
anticoagulation is necessarily withhel, such as uring surgery
or elivery, or i VE evelops in an anticoagulate woman,
treatment with recombinant human antithrombin may be protective (Paias, 2016).
Protein C Deficiency
When thrombin is boun to thrombomoulin on enothelial
cells o small vessels, its procoagulant activities are neutralize.
Tis bining also activates protein C, a natural anticoagulant.
It, in the presence o protein S, controls thrombin generation,
in part, by inactivating actors Va an VIIIa (see Fig. 55-1).
Protein C activity increases moestly but signicantly throughout the rst hal o pregnancy, an some have speculate that
this augmentation may play a role in maintaining early pregnancy through both anticoagulant an inammatory regulatory
pathways (Sai, 2010).
coworkers (2020) ha similar observations or women with preeclampsia. Risks were signicantly higher among women who
ha a stillbirth or who unerwent peripartum hysterectomy.
Last, as iscusse in Chapter 57 (p. 1021), inammatory bowel
isease increases the risk two- to threeol (Kim, 2019).
THROMBOPHILIAS
Several important regulatory proteins act as inhibitors in the
coagulation cascae (Fig. 55-1). Normal values or many o
these proteins uring pregnancy are oun in the Appenix
(p. 1228). Inherite or acquire eciencies o these inhibitory proteins are collectively reerre to as thrombophilias. Tese
can lea to hypercoagulability an recurrent VE (Connors,
2017). Although these isorers are collectively present in
approximately 15 percent o white European populations, they
are responsible or approximately 50 percent o all thromboembolic events uring pregnancy (Pierangeli, 2011). Some aspects
o the more common inherite thrombophilias relate to VE
are summarize in Table 55-2.
■ Inherited Thrombophilias
Patients with inherite thrombophilic isorers oten have a
amily history o thrombosis. Tese mutations are also oun in
up to hal o all patients who present with VE beore the age
o 45 years, particularly in those whose event occurre in theThromboembolic Disorders 977
CHAPTER 55
TABLE 55-2. Inherited Thrombophilias and Their Association with Venous
Thromboembolism (VTE) in Pregnancy
VTE Risk per Pregnancy (%)
No History Prior VTE Family History
Factor V Leiden heterozygote 0.5–3.1 10 0.06–1.2
Factor V Leiden homozygote 2.2–1.4 17 1–16
Prothrombin gene heterozygote 0.4–2.6 >10 0–0.73
Prothrombin gene homozygote 2–4 >17 1.6
Factor V Leiden/prothrombin double
heterozygote
8.2 >20 0–2.4
Antithrombin deficiency 0.2–1.16 40 0–8
Protein C deficiency 0.1–5.4 4–17 0–5
Protein S deficiency 0.1–6.6 0–22 0–1.5
Hyperhomocysteinemia 0 0 <1
Data from Abbattista, 2020; American College of Obstetricians and
Gynecologists, 2020a; Bates, 2018; Croles, 2017.
Protein S
deficiency
Inactivates
factor Va
Inactivates
factor VIIIa
PROTEIN S PROTEIN S
Protein C
deficiency
Factor V Leiden mutation
Factor V resistant to
degradation by protein C
Hyperhomocysteinemia
(inhibits activation of protein C)
G20210A mutation
Increased prothrombin
levels
Antithrombin deficiency
Controls thrombin
generation
Decreased thrombin
neutralization
Thrombin binds to
thrombomodulin on
endothelial cells
Activated protein C Protein C
Prothrombin Thrombin Coagulation
FIGURE 55-1 Inherited thrombophilias and their effect(s) on the coagulation cascade.978
Section 12
Medical and Surgical Complications
More than 160 ierent autosomal ominant mutations
or the protein C gene have been escribe (Louis-Jacques,
2016). Te prevalence o heterozygous protein C eciency is
2 to 3 per 1000, but many o these iniviuals o not have a
thrombosis history because the phenotypic expression is highly
variable. Tese prevalence estimates correspon with unctional
activity threshol values o 50 to 60 percent, which are use
by most laboratories. As shown in able 55-2, these are associate with a six- to twelveol higher risk or VE (Lockwoo,
2012). Te rare cases o homozygous protein C eciency may
cause atal neonatal purpura ulminans. Last, sepsis can result
in purpura ulminans in the ault with heterozygous protein C
eciency (Benapui, 2021).
Protein S Deficiency
Tis circulating anticoagulant is activate by protein C, which
enhances the capacity o protein S to inactivate actors Va an
VIIIa (see Fig. 55-1). Protein S eciency may be cause by
more than 130 ierent mutations, with an aggregate heterozygous prevalence o approximately 0.3 to 1.3 per 1000 iniviuals (Louis-Jacques, 2016). Protein S eciency may be measure
by antigenically etermine ree, unctional, an total S levels.
All three ecline substantively uring normal gestation (Appen-
ix, p. 1228). Tus, the iagnosis in pregnant women—as well
as in those taking certain oral contraceptives—is ifcult. I
screening uring pregnancy is necessary, threshol values or
ree protein S antigen levels in the secon an thir trimesters
have been ientie at <30 percent an <24 percent, respectively. Te risk o VE in pregnancy is increase severalol
(see able 55-2). Among those with a positive amily history,
the VE risk in pregnancy is 6 to 7 percent (American College
o Obstetricians an Gynecologists, 2020a).
Conar an coworkers (1990) escribe thrombosis in ve
o 29 pregnant women with protein S eciency. Tey, as well
as Burneo an colleagues (2002), reporte maternal cerebral
vein thrombosis. Neonatal homozygous protein S eciency
is usually associate with purpura ulminans, the atal clinical
phenotype.
Factor V Leiden Mutation
Tis is the most prevalent o the known thrombophilia syn-
romes an is characterize by resistance o plasma to the
anticoagulant eects o activate protein C. Tere are several
mutations that create this resistance, but the most common is
the actor V Leien mutation. Tis missense mutation results
rom a substitution o glutamine or arginine at position 506
in the actor V polypeptie. As a result o this mutation, activate actor V is neutralize approximately tenol more slowly
by activate protein C (see Fig. 55-1). Tis leas to enhance
thrombin generation.
Heterozygous inheritance o actor V Leien is the most
common heritable thrombophilia. It is oun in 3 to 15 percent
o select European populations, 1.2 percent o Arican Americans, an 2.2 o Hispanic Americans, but is virtually absent in
Arican blacks an Asians (American College o Obstetricians
an Gynecologists, 2020a). Women who are heterozygous
or actor V Leien account or approximately 40 percent o
VE cases uring pregnancy. However, the actual risk among
pregnant women who are heterozygous an who o not have a
personal history or a rst-egree relative with a thrombotic episoe beore age 50 years is 5 to 12 events per 1000 births (see
able 55-2). In contrast, this risk is at least 10 percent among
pregnant women with a personal or amily history. Pregnant
women who are homozygous without a personal or amily history have a 1- to 4-percent risk or VE, whereas those with
such a history have an approximately 17-percent risk (American College o Obstetricians an Gynecologists, 2020a).
Diagnosis uring pregnancy is perorme by DNA analysis or the mutant actor V gene. Bioassay is not use because
o the normal resistance that evelops ater early pregnancy
rom alterations in other coagulation protein concentrations.
O note, activate protein C resistance can also be cause by
antiphospholipi synrome, which is escribe on page 979
an also etaile in Chapter 62 (p. 1114).
o assess the prognostic signicance o maternal actor V
Leien mutation uring pregnancy, Kjellberg an associates
(2010) compare the outcomes o 491 carriers with those o
1055 controls. All three o the thromboembolic events occurre
among the carriers. But, preterm birth rates, birthweights, or
hypertensive complication rates i not ier between the two
groups. In a prospective observational stuy o almost 5000
women conucte by the Maternal-Fetal Meicine Units Network, the heterozygous mutant gene incience was 2.7 percent
(Dizon-ownson, 2005). O three pulmonary emboli an one
eep-vein thrombosis cases—a rate o 0.8 per 1000 pregnancies—none was among these carriers. Moreover, in the heterozygous women, the risks o preeclampsia, placental abruption,
etal-growth restriction, or pregnancy loss were not elevate.
Te investigators conclue that universal prenatal screening
or the Leien mutation an prophylaxis or carriers without a
prior VE is not inicate.
Prothrombin G20210A Mutation
Tis missense mutation in the prothrombin gene leas to excessive accumulation o prothrombin, which may be converte
to thrombin. Prothrombin levels are increase approximately
30 percent in heterozygotes an 70 percent in homozygotes
(MacCallum, 2014). As with actor V Leien, a personal or
amily history o VE in a rst-egree relative beore age 50
years raises the risk o VE uring pregnancy (see able 55-2).
For a heterozygous carrier with such a history, the risk excees
10 percent. Without such a history, heterozygous carriers o
the mutation have less than a 1-percent risk o VE uring
pregnancy (American College o Obstetricians an Gynecologists, 2020a).
Silver an coworkers (2010) teste nearly 4200 women
or the prothrombin G20210A mutation. A total o 157—or
3.8 percent—o the women carrie the mutation, an only
one o these was homozygous. Carriers ha similar rates o
pregnancy loss, preeclampsia, etal-growth restriction, an placental abruption compare with noncarriers. Tree thromboembolic events occurre in women who teste negative or the
mutation.
Homozygous patients, or those who are oubly heterozygous or a G20210A mutation with a actor V Leien mutation, have a greater thromboembolism risk than heterozygousThromboembolic Disorders 979
CHAPTER 55
carriers (Connors, 2017). Others have provie etaile inormation on pregnancy outcomes in women with such rare compoun thrombophilias (Carroll, 2018; Lim, 2016).
Hyperhomocysteinemia
Te most common cause o elevate homocysteine is the
C667 thermolabile mutation o the 5, 10– methylene–tetrahyroolate reuctase (MHFR) enzyme. Inheritance is autosomal recessive. Elevate homocysteine levels may also result
rom eciency o one o several enzymes involve in methionine metabolism an rom correctible nutritional eciencies
o olic aci, vitamin B6, or vitamin B12. During normal pregnancy, mean homocysteine plasma concentrations ecline an
make a iagnosis ifcult (Lockwoo, 2002).
A metaanalysis by en Heijer an associates (2005) reporte
an association between MHFR polymorphisms an a slightly
greater risk or thrombosis in international stuies, but no such
association was oun in North American stuies (en Heijer,
2005). Te authors speculate that olic aci supplementation coul explain the ierence. Recall that olic aci serves
as a coactor in the remethylation reaction o homocysteine to
methionine. Similarly, the American College o Chest Physicians posite that the lack o an association with thromboembolism coul reect the physiological reuctions in homocysteine
levels associate with pregnancy as well as the eects o wiesprea prenatal olic aci supplementation (Bates, 2012). Te
American College o Obstetricians an Gynecologists (2020a)
has conclue that there is insufcient evience to support
assessment o MHFR polymorphisms or measurement o
asting homocysteine levels in the evaluation or VE.
Other Thrombophilia Mutations
Protein Z is a vitamin K–epenent protein that serves as a
coactor in actor Xa inactivation. Stuies have oun that low
protein Z levels are associate with an elevate thromboembolism risk in nonpregnant patients an may be implicate in
the pathogenesis o poor pregnancy outcomes (Almawi, 2013).
Similarly, plasminogen activator inhibitor type 1 (PAI-I) is an
important regulator o brinolysis. Certain polymorphisms in
the gene promoter have been associate with slightly higher
VE risks. Although these thrombophilias may exacerbate risk
among patients when coinherite with other thrombophilias, the American College o Obstetricians an Gynecologists
(2020a) has conclue that evience to recommen screening
is insufcient.
■ Acquired Thrombophilias
Some examples o acquire hypercoagulable states inclue
antiphospholipi synrome (APS), heparin-inuce thrombocytopenia, an cancer.
Antiphospholipid Syndrome
Tis prothrombotic isorer can aect both the venous an
arterial circulations. Te eeper veins o the lower limbs an
the cerebral arterial circulation are the most requent sites o
venous an arterial thrombosis, respectively (Garcia, 2018;
Konkle, 2018). Besies thrombosis, the other major clinical
maniestations o APS are averse obstetrical outcomes (able
11-4, p. 205). Criteria or APS inclue (1) at least one otherwise unexplaine etal eath at or beyon 10 weeks; (2) at
least one preterm birth beore 34 weeks’ gestation because o
eclampsia, severe preeclampsia, or placental insufciency; or (3)
at least three unexplaine consecutive spontaneous abortions
beore 10 weeks. Te synrome is iscusse in etail in Chapter
62 (p. 1114).
esting or antiphospholipi antiboies shoul be per-
orme in women with an unexplaine arterial or venous
thromboembolism or a history o one etal loss or three or
more recurrent embryonic or etal losses (American College
o Obstetricians an Gynecologists, 2020a). At this time, preterm severe preeclampsia an early-onset placental insufciency
o not support such testing. Tat sai, there is evience that
antiphospholipi positivity coners a worse prognosis or pregnancies complicate by HELLP synrome (Pécourt, 2021).
Tese patients shoul be teste or the presence o three actors:
(1) lupus anticoagulant, (2) anticariolipin immunoglobulin G
an M (IgG an IgM) antiboies, an (3) anti-β2 glycoprotein-I
IgG an IgM antiboies. I any o these laboratory test results
are positive, a conrmatory test is perorme 12 weeks later
(Connors, 2017).
Base on their stuy o 750 singleton pregnancies complicate by APS, Saccone an colleagues (2017) oun that
anticariolipin antiboy is the most common sole antiphospholipi antiboy present. Women with APS have a 5- to
12-percent risk o thrombosis uring pregnancy or the puerperium. Inee, up to 25 percent o these thrombotic events
occur uring pregnancy or in the puerperium.
■ Thrombophilias and Pregnancy
Complications
Contrary to past teaching, no enite causal link between
inherite thrombophilias an averse pregnancy outcomes
exists (Ormesher, 2017). Te conusion was cause by a number o observational stuies that were later ollowe by large
prospective cohort stuies. Currently, the American College o
Obstetricians an Gynecologists (2020a) oes not recommen
inherite thrombophilia screening or women with a history o
etal loss or averse pregnancy outcomes such as etal-growth
restriction, placental abruption, an preeclampsia.
Tere are no convincing ata that link inherite thrombophilias an etal loss. It ollows that there is no benet to aspirin or heparin therapy as might accrue or recurrent pregnancy
loss ue to antiphospholipi antiboies (Chap. 62, p. 1116).
Stillbirths also are not more common with heterozygous mutations, but there is a weak association with homozygous actor
V Leien mutation (Silver, 2016). Last, there is insufcient evi-
ence to screen or inherite thrombophilias in women with a
etal eath (Arachchillage, 2019).
Fetal-growth restriction also is not more common with inherite thrombophilias (American College o Obstetricians an
Gynecologists, 2020a; Inante-Rivar, 2002). Likewise, there
have been a number o prospective cohort stuies that showe
no association o inherite thrombophilias with placental
abruption (Dizon-ownson, 2005; Silver, 2010). Conversely,980
Section 12
Medical and Surgical Complications
Alrevic an coworkers (2002) reporte an association with
these an both heterozygosity an homozygosity or actor V Leien mutations as well as heterozygous prothrombin
G20210A mutation.
Stuies showing an association o inherite thrombophilias
an preeclampsia also are conicting (American College o Obstetricians an Gynecologists, 2020a). One large systematic review
an metaanalysis o nearly 22,000 women i not show an association between actor V Leien or prothrombin gene mutations
with preeclampsia (Roger, 2010). Similarly, a more recent prospective stuy aile to show an association between preeclampsia
an 12 hereitary thrombophilias (Fernanez Arias, 2019).
Tus, because o uncertainties in the magnitue o risk an
in the benets o prophylaxis given to prevent pregnancy complications in women with heritable thrombophilias, it remains
unproven that universal screening is inicate (Louis-Jacques,
2016). In contrast, the association between APS an averse
pregnancy outcomes—incluing etal loss, recurrent pregnancy
loss, an preeclampsia—is much stronger (Liu, 2019).
■ Thrombophilia Screening
Given the relatively high incience o thrombophilia in the
population an the low incience o VE, universal screening
uring pregnancy is not cost-eective. Tus, a selective screening strategy is require. Te American College o Obstetricians
an Gynecologists (2020a) recommens that thrombophilia
screening be consiere in the ollowing clinical circumstances:
(1) a personal history o VE with or without a recurrent risk
actor such as ractures, surgery, or prolonge immobilization;
an (2) a rst-egree relative (parent or sibling) with a history
o a high-risk inherite thrombophilia. As iscusse previously,
testing or inherite thrombophilias in women who have experience recurrent etal loss or averse pregnancy outcomes is
not recommene.
Methos o screening or the more common inherite
thrombophilias are shown in Table 55-3. Whenever possible, laboratory testing is perorme at least 6 weeks ater the
thrombotic event, while the patient is not pregnant, an when
she is not receiving anticoagulation or hormonal therapy. Last,
screening or hyperhomocysteinemia is not recommene
(American College o Obstetricians an Gynecologists, 2020a).
DEEP-VEIN THROMBOSIS
■ Clinical Presentation
During pregnancy, most venous thromboses are conne to
the eep veins o the lower extremity. Most o these are locate
in the ilioemoral an iliac veins without involvement o the
cal veins (Chan, 2010). In contrast, in the general population, more than 80 percent o eep-vein thromboses involve
cal veins (Huisman, 2015). Te vast majority are let sie
(Blanco-Molina, 2007). Greer (2003) hypothesizes that this
results rom compression o the let iliac vein by the right iliac
an ovarian arteries, both o which cross the vein only on the
let sie. Yet, as escribe in Chapter 56 (p. 994), the ureter is
compresse more on the right sie.
Signs an symptoms vary epening on the egree o occlusion an the intensity o the inammatory response. Classically,
thrombosis involving the lower extremity is abrupt in onset, an
there is pain an eema o the leg an thigh. Te thrombus
typically involves much o the eep-venous system to the ilio-
emoral region. Occasionally, reex arterial spasm causes a pale,
cool extremity with iminishe pulsations. Cal measurements
may ientiy a iscorance in size. Alternatively, there may be
appreciable clot, yet little pain, heat, or swelling. Importantly,
cal pain, either spontaneous or in response to squeezing or to
Achilles tenon stretching—Homans sign—may be cause by a
straine muscle or contusion. Importantly, 30 to 60 percent o
women with a confrmed lower-extremity acute deep-vein thrombosis (DVT) have an asymptomatic pulmonary embolism (p. 986).
■ Diagnosis
Clinical iagnosis o DV is ifcult without testing an is
conrme in only 10 percent o cases (Hull, 1990). Another
TABLE 55-3. How to Test for Thrombophilias
Thrombophilia Testing Method
Is Testing
Reliable
During
Pregnancy?
Is Testing
Reliable
During Acute
Thrombosis?
Is Testing
Reliable with
Anticoagulation?
Factor V Leiden mutation Activated protein C resistance
assay (second generation)
If abnormal: DNA analysis
Yes
Yes
Yes
Yes
No
Yes
Prothrombin gene mutation G20210A DNA analysis Yes Yes Yes
Protein C deficiency Protein C activity (<65%) Yes No No
Protein S deficiency Functional assay (<55%) Noa No No
Antithrombin deficiency Antithrombin activity (<60%) Yes No No
aIf screening in pregnancy is necessary, cutoff values for free protein S antigen levels in the second and third trimesters have
been identified at less than 30% and less than 24%, respectively.
Reproduced with permission from American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–
Obstetrics. ACOG Practice Bulletin No. 197: Inherited Thrombophilias in Pregnancy, Obstet Gynecol 2018 Jul;132(1):e18-e34.Thromboembolic Disorders 981
CHAPTER 55
challenge is that many o the
common iagnostic tests that
have been investigate extensively in nonpregnant patients
have not been valiate appropriately in pregnancy (Huisman,
2015). Shown in Figure 55-2
is one iagnostic algorithm that
can be use or evaluation o
pre gnant women. With a ew
moications, we ollow a
similar evaluation at Parklan
Hospital.
Compression
Ultrasonography
With suspecte DV, the initial
iagnostic test recommene is
compression ultrasonography o
the proximal leg veins (American College o Obstetricians
an Gynecologists, 2020b). Te
iagnosis is base on the noncompressibility an typical echoarchitecture o a thrombose
vein. For nonpregnant patients
with suspecte thrombosis, the
saety o withholing anticoagulation or 1 week has been establishe in the setting o a normal
compression ultrasoun examination (Birwell, 1998). Serial
compression examinations are
then perorme because isolate
unetecte cal thromboses that
ultimately exten into the proximal veins will o so within 1 to
2 weeks o presentation in approximately a ourth o patients.
In pregnant women, however, normal nings with ultrasonography o not always exclue a pulmonary embolism. Tis is
because the thrombosis may have alreay embolize or because
it arose rom iliac or other eep-pelvic veins, which are less accessible to ultrasoun evaluation.
wo stuies are helpul or evaluating whether serial
examinations are necessary or pregnant women suspecte
o having a DV. Chan an associates (2013) stuie 221
pregnant an postpartum women presenting with a suspecte
DV. Te 205 women with a negative initial stuy result
unerwent serial testing, which was negative in all cases. O
these, one woman ha a pulmonary embolism 7 weeks later.
Le Gal an colleagues (2012) stuie 210 pregnant an postpartum women with a suspecte DV. O these, 177 women
without a DV were not anticoagulate an i not unergo
serial testing. wo ha an objectively conrme thrombosis
iagnose within 3 months. In sum, these ata suggest that a
negative single complete compression ultrasonography stuy
may saely exclue the iagnosis o DV in most pregnant
women.
FIGURE 55-2 Algorithm to evalate suspected venous thromboembolism in pregnancy depending upon number of YEARS criteria met. Evidence of DVT should prompt compression ultrasound.
aThe three YEARS criteria are clinical signs of DVT, hemoptysis, and PE as the most likely diagnosis.
bThe American Thoracic Society and Society of Thoracic Radiology recommend CXR; cThe American
Society of Hematology recommends pulmonary V/Q scanning. CT = computed tomography;
CTA = computed tomography angiography; CXR = chest x-ray; DVT = deep-vein thrombosis;
MR = magnetic resonance; PE = pulmonary embolism; V/Q scan = ventilation perfusion scan.
(From Bates, 2018; Guyatt, 2012; Leung, 2011; van der Hulle, 2019; van der Pol, 2019.)
Magnetic Resonance Imaging
Tis imaging technique allows excellent elineation o anatomical etail above the inguinal ligament. Tus, in many
cases, magnetic resonance (MR) imaging is immensely useul
or iagnosis o ilioemoral an pelvic vein thrombosis. Te
venous system can also be reconstructe using MR venography (Chap. 49, p. 875). MR imaging is 100-percent sensitive
an 90-percent specic or etection o venographically proven
DV in nonpregnant patients (Erman, 1990). Importantly,
almost hal o those without DV were oun to have nonthrombotic conitions that inclue cellulitis, myositis, eema,
hematomas, an supercial phlebitis.
d-dimer Screening Tests
Tese specic brin egraation proucts are generate when
brinolysin (plasminogen) egraes brin, as occurs in thromboembolism. Teir measurement is usually incorporate into
iagnostic algorithms or VE in nonpregnant patients (Righini,
2018). Tis metho was shown to be accurate in the YEARS stuy
(van er Hulle, 2017). Screening with the d-imer test in pregnancy, however, is problematic or several reasons. Depening982
Section 12
Medical and Surgical Complications
on assay sensitivity, d-imer serum levels rise with gestational
age along with substantively elevate plasma brinogen concentrations (Appenix, p. 1228) (Johnson, 2019). Levels are also
aecte by multietal gestation an cesarean elivery (Hu, 2020;
Miyamoto, 2020). Last, d-imer concentrations can also be elevate in pregnancy complications such as placental abruption,
preeclampsia, an sepsis (Cunningham, 2015).
Tree large prospective stuies have evaluate d-imer testing in pregnant women to iagnose VE. Righini an colleagues (2018) oun that d-imer measurement, bilateral leg
ultrasoun, an compute tomography-angiogram saely rule
out VE. Subsequently, van er Pol an coworkers (2019)
use a pregnancy-aapte YEARS algorithm to iagnose suspecte pulmonary embolism. Te algorithm use d-imer
measurements an clinical suspicion to conrm VE. With
none o the clinical criteria present, an with the d-imer level
<1000 ng/mL, or with one or more clinical criteria present an
with the d-imer level <500 ng/mL, pulmonary embolism was
saely exclue (see Fig. 55-2). Last, the DiPEP stuy showe
that neither clinical risk actors nor d-imer levels were accurate in ientiying pulmonary embolism in pregnant women
(Gooacre, 2019). Tey conclue that pregnant women with
suspecte pulmonary embolism shoul all unergo imaging
stuies.
TABLE 55-4. Anticoagulation Regimen Definitions
Anticoagulation Regimen Definition
Prophylactic LMWHa Enoxaparin, 40 mg SC once daily
Dalteparin, 5000 units SC once daily
Nadroparin, 2850 units SC once daily
Tinzaparin, 4500 units SC once daily
Therapeutic LMWHb Enoxaparin, 1 mg/kg every 12 hours
Dalteparin, 200 units/kg once daily
Tinzaparin, 175 units/kg once daily
Dalteparin, 100 units/kg every 12 hours
Target an anti-Xa level in the therapeutic range of 0.6–1.0 units/mL 4 hours after last injection
for twice daily regimen; slightly higher doses may be needed for a once-daily regimen.
Prophylactic UFH UFH, 5000–7000 units SC every 12 hours in first trimester
UFH 7500–10,000 units SC every 12 hours in the second trimester
UFH, 10,000 units SC every 12 hours in the third trimester, unless the aPTT is elevated
Adjusted dose
(therapeutic) UFHb
UFH, 10,000 units or more SC every 12 hours in doses adjusted to target aPTT in the
therapeutic range (1.5–2.5 × control) 6 hours after injection
Postpartum
anticoagulation
Prophylactic, intermediate, or adjusted-dose LMWH for 6–8 weeks as indicated. Oral
anticoagulants may be considered postpartum based upon planned duration of therapy,
lactation, and patient preference.
Surveillance Clinical vigilance and appropriate objective investigation of women with symptoms suspicious
of deep vein thrombosis or pulmonary embolism. VTE risk assessment should be performed
prepregnancy or early in pregnancy and repeated if complications develop, particularly
those necessitating hospitalization or prolonged immobility.
aAlthough at extremes of body weight, modification of dose may be required.
bAlso referred to as weight adjusted, full treatment dose.
aPTT = activated partial thromboplastin time; INR = international normalized ratio; LMWH = low-molecular-weight heparin;
SC = subcutaneously; UFH = unfractionated heparin.
Reproduced with permission from American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–
Obstetrics. ACOG Practice Bulletin No. 197: Inherited Thrombophilias in Pregnancy, Obstet Gynecol 2018 Jul;132(1):e18-e34.
Te nings o the YEARS stuy an subsequent others
will no oubt guie care. However, currently the American
College o Obstetricians an Gynecologists (2020b) recommens
against the use o d-imer assays to iagnose VE in pregnant
women. We agree, an in our view, these positive results nee to
be uplicate beore aaptation o their wiesprea use in pregnant women. Still, a negative d-imer assay shoul be reassuring,
unless VE is the most likely iagnosis (Viau-Lapointe, 2020).
■ Management of Venous Thromboembolism
Optimal management o VE uring pregnancy has not unergone major clinical stuy to provie evience-base practices.
Tere is, however, consensus or treatment with anticoagulation
an limite activity. Trombophilia testing oes not change
treatment (Connors, 2017). Anticoagulation is initiate with
either unractionate heparin (UFH) or LMWH (Table 55-4).
Although either type is acceptable, most recommen one o the
LMWHs (American College o Obstetricians an Gynecologists, 2020b; Kearon, 2016). Te American Society o Hematology recommens preerential use o LMWH uring pregnancy
because o better bioavailability, longer plasma hal-lie, more
preictable ose response, reuce risks o osteoporosis an
thrombocytopenia, an less requent osing (Bates, 2018).Thromboembolic Disorders 983
CHAPTER 55
Te uration o ull anticoagulation varies, an no stu-
ies have ene the optimal uration or pregnancy-relate
thromboembolism. In nonpregnant patients, evience supports a minimum treatment uration o 3 months (Kearon,
2012). For pregnant patients, the American College o Obstetricians an Gynecologists (2020b) recommens therapeutic
anticoagulation or 3 to 6 months ollowe by intermeiate
or prophylactic therapy or the uration o pregnancy an the
postpartum perio. I the woman is not breasteeing, irect
acting oral agents can be consiere (p. 985).
Recall that pulmonary embolism evelops in as many as 60
percent o patients with untreate venous thrombosis, an anticoagulation ecreases this risk to less than 5 percent. In nonpregnant patients, the mortality rate with a pulmonary embolism
approximates 1 percent (Douketis, 1998; Pollack, 2011).
With DV, over several ays, leg pain issipates. Ater
symptoms have abate, grae ambulation is begun. Elastic
stockings are tte, an anticoagulation is continue. Recovery
to this stage usually takes 7 to 10 ays. Grauate compression
stockings can be continue or 2 years ater the iagnosis to
reuce the incience o postthrombotic synrome (Branjes,
1997). Symptoms inclue chronic leg paresthesias or pain,
intractable eema, skin changes, an leg ulcers. Accoring to
the American Society o Hematology, catheter-irecte thrombolytic therapy oes not mitigate against this complication
(Bates, 2018).
Unfractionated Heparin
Tis agent shoul be consiere or the initial treatment o
thromboembolism an in situations in which elivery, surgery,
or thrombolysis may be necessary (American College o Obstetricians an Gynecologists, 2020b). UFH can be aministere
by one o two alternatives: (1) initial intravenous therapy ollowe by ajuste-ose subcutaneous UFH given every 12
hours; or (2) twice-aily, ajuste-ose subcutaneous UFH
with oses ajuste to prolong the activate partial thromboplastin time (aP) into the therapeutic range 6 hours post
injection (Table 55-5).
For intravenous therapy, several protocols are acceptable.
In general, i UFH is use, it is initiate with a bolus intravenous ose o 70 to 100 U/kg, which is 5000 to 10,000 U.
Tis is ollowe by continuous intravenous inusions beginning at 1000 U/hr or 15 to 20 U/kg/hr. Tis inusion rate is
titrate to achieve an aP 1.5 to 2.5 times control values
(Linnemann, 2016). Intravenous anticoagulation is maintaine or about 5 to 7 ays, ater which treatment is converte to subcutaneous heparin to maintain the aP to at
least 1.5 to 2.5 times control throughout the osing interval.
For women with lupus anticoagulant, aP oes not accurately assess heparin anticoagulation, an thus anti–actor Xa
levels are preerre.
Low-molecular-weight Heparin
Tis is a amily o erivatives o unractionate heparin, an
their molecular weights average 4000 to 5000 altons compare with 12,000 to 16,000 altons or conventional heparin.
None o these heparins cross the placenta, an all exert their
anticoagulant activity by activating antithrombin. UFH has
equivalent activity against actor Xa an thrombin compare
with LMWHs, which have greater activity against actor Xa
than against thrombin. Tey also have a more preictable
anticoagulant response an ewer bleeing complications than
UFH because o their better bioavailability, longer hal-lie,
ose-inepenent clearance, an ecrease intererence with
platelets (American College o Obstetricians an Gynecologists,
2020b; Bates, 2018). Teir longer hal-lie prohibits neuraxial
analgesia in laboring women. LMWH compouns are cleare
by the kineys an must be use cautiously when there is renal
ysunction.
Several stuies have shown that VE is treate eectively
with LMWH (Quinlan, 2004; apson, 2008). Using serial
venograms, Brein an associates (2001) observe that these
compouns were more eective than UFH in reucing thrombus size without increasing mortality rates or major bleeing
complications. Several ierent treatment regimens using
LMWH or treatment o acute VE are liste in able 55-4
(American College o Obstetricians an Gynecologists, 2020b).
Whether LMWH requires ajustments uring the course
o pregnancy is controversial (Berresheim, 2014). Te American College o Obstetricians an Gynecologists (2020b) recommens monitoring with an anti-Xa level 4 hours ater an
injection with ose ajustment to maintain a therapeutic
level. Large stuies using clinical en points that emonstrate
an optimal therapeutic range or show that ose ajustments
increase therapy, saety, or efcacy are lacking. Accoringly, the
American Society o Hematology an others have conclue
that routine monitoring with anti-Xa levels is ifcult to justiy
(Bates, 2018; McDonnell, 2017).
In general, heparin pharmacokinetics inclues more rapi
clearance o heparins as pregnancy progresses. Te peaks o
anti-Xa activity o enoxaparin (Lovenox) across pregnancy are
shown in Figure 55-3. Similarly, tinzaparin (Innohep) with a
osage o 75 to 175 U/kg/ was necessary to achieve peak anti–
actor Xa levels o 0.1 to 1.0 U/mL (Smith, 2004). In stuies
FIGURE 55-3 Anti–factor Xa activity with repeated daily administration of 40 mg enoxaparin subcutaneously in nonpregnant
women and those from each trimester (Data from Lebaudy, 2008).984
Section 12
Medical and Surgical Complications
TABLE 55-5. Some Recommendations for Thromboprophylaxis During Pregnancy
Clinical Scenario
Pregnancy Postpartum
ACOGa ASHb ACOGa ASHb
Prior single VTE
Risk factor no longer
present
Surveillance only Surveillance
only
Surveillance or prophylactic
heparin with additional
risk factorsf
Prophylactic or
intermediatedose heparin
Pregnancy- or estrogenrelated or no known
association
Prophylactic or
intermediate-dose
heparin
Prophylactic or
intermediatedose heparin
Prophylactic, intermediate,
or therapeutic-dose
heparin
Prophylactic or
intermediatedose heparin
Associated with a highrisk thrombophiliad or
affected first-degree
relative
Prophylactic, intermediate,
or therapeutic-dose
heparin
NSS Prophylactic, intermediate,
or therapeutic-dose
heparin
Prophylactic or
intermediatedose heparin
Associated with
a low-risk
thrombophiliae
Prophylactic or
intermediate-dose
heparin
NSS Prophylactic or
intermediate-dose
heparin
Prophylactic or
intermediatedose heparin
Two or more prior VTEs with or without thrombophilia
Not receiving
long-term
anticoagulation
Intermediate or therapeuticdose heparin
NSS Intermediate or therapeuticdose heparin
Prophylactic or
intermediatedose heparin
Receiving long-term
anticoagulation
Therapeutic-dose heparin Therapeuticdose heparin
Resume long-term
anticoagulation
Resume long-term
anticoagulation
No prior VTE
No thrombophilia Surveillance NSS Surveillance or prophylactic
heparin with additional
risk factorsf
NSS
High-risk
thrombophilia
Surveillance only or
prophylactic-dose heparin
Surveillance Prophylactic or intermediatedose heparin
Prophylactic
heparin
Positive family history
VTE and low-risk
thrombophiliac
Surveillance or prophylacticdose heparin
Surveillance Prophylactic or
intermediate-dose
heparin
Surveillance
Low-risk
thrombophilia
Surveillance Surveillance Surveillance; prophylacticdose heparin with
additional risk factorsf
Surveillance
Compound
heterozygous
thrombophilia
Prophylactic or
intermediate-dose
heparin
Prophylactic
heparin
Prophylactic or
intermediate-dose
heparin
Prophylactic
heparin
Antiphospholipid antibodies
History of VTE Prophylactic heparin (?plus
low-dose aspirin)
NSS Prophylactic heparin;
referral to specialistg
NSS
No prior VTE Surveillance or prophylactic
heparin plus low-dose
aspirin with recurrent
pregnancy loss or stillbirthf
NSS Prophylactic heparin plus
low-dose aspirin × 6 weeks
with recurrent pregnancy
loss or stillbirthg
NSS
aAmerican College of Obstetricians and Gynecologists 2020a,b.
bAmerican Society of Hematology (Bates, 2018).
cPostpartum treatment levels should be ≥ antepartum treatment.
dAntithrombin deficiency; doubly heterozygous or homozygous for prothrombin 20210A and factor V Leiden.
eHeterozygous factor V Leiden or prothrombin 20210A; protein S or C deficiency.
fFirst-degree relative with VTE at <50 years; other major thrombotic risk factors, e.g., obesity, prolonged immobility.
gWomen with antiphospholipid syndrome should not use estrogen-containing contraceptives.
hTreatment is recommended if the diagnosis of antiphospholipid syndrome is based on three or more prior pregnancy losses.
NSS = not specifically stated; VTE = venous thromboembolism.
Prophylactic, intermediate-, and adjusted-dose regimens are listed in Table 55-4.Thromboembolic Disorders 985
CHAPTER 55
o alteparin (Fragmin) pharmacokinetics, conventional starting oses o alteparin—100 U/kg every 12 hours—were
likely insufcient to maintain ull anticoagulation in pregnant
women (Barbour, 2004; Jacobsen, 2003). Tus, slightly higher
oses than that shown in able 55-4 may be require.
Any concerns regaring teratogenicity o enoxaparin have
been obviate (American College o Obstetricians an Gynecologists, 2020b; Bates, 2021). A comprehensive stuy o 1267
pregnant women treate with tinzaparin oun no cases o heparin-inuce thrombocytopenia, maternal eaths, or complications rom regional analgesia (Nelson-Piercy, 2011). A total
o 43 women (3.4 percent) require meical intervention or
bleeing. O 15 stillbirths, our were juge as possibly being
relate to tinzaparin use. LMWHs have been juge to be sae
uring breasteeing (Bates, 2018).
Labor and Delivery
Women receiving either therapeutic or prophylactic anticoagulation shoul be converte rom LMWH to the shorter-hal-
lie UFH in the last month o pregnancy or sooner i elivery
appears imminent. Te purpose o conversion to UFH has less
to o with any risk o maternal bleeing at the time o elivery,
but rather with neuraxial blockae complicate by an epi-
ural or spinal hematoma (Chap. 25, p. 478). Te Society or
Obstetric Anesthesia an Perinatology recommens that UFH
low-ose thromboprophylaxis be withhel or 4 to 6 hours;
UFH intermeiate-ose thromboprophylaxis or 12 hours; an
UFH therapeutic ose or 24 hours beore neuraxial analgesia
(Leert, 2018). For LMWH, the Society recommens to withhol low oses or 12 hours; intermeiate oses 12 to 24 hours;
an therapeutic oses 24 hours.
I a woman begins labor while taking UFH, clearance can
be verie by an aP. Reversal o heparin with protamine
sulate—1 mg per 100 units heparin with a maximum ose o
50 mg—is rarely require an is not inicate with a prophylactic ose o heparin. For women in whom anticoagulation
therapy has temporarily been iscontinue, pneumatic compression evices are recommene.
Warfarin Compounds
Vitamin K antagonists are generally contrainicate because they
reaily cross the placenta an cause etal eath an malormations
rom hemorrhages. Tis is iscusse in etail in Chapter 8 (p.
156). Teir sole antepartum use is in women with a mechanical
heart valve (Daughety, 2020). Tese compouns o not accumulate in breast milk an are thus sae uring breasteeing.
Postpartum venous thrombosis is usually treate with intravenous heparin an oral wararin initiate simultaneously. Te
initial ose o wararin is 5 to 10 mg or the rst 2 ays. Subsequent oses are titrate to achieve an international normalize
ratio (INR) o 2 to 3. o avoi paraoxical thrombosis an
skin necrosis rom the early antiprotein C eect o wararin,
these women are maintaine on therapeutic oses o UFH or
LMWH or 5 ays an until the INR is in a therapeutic range
or 2 consecutive ays (American College o Obstetricians an
Gynecologists, 2020b).
reatment in the puerperium may require larger oses
o anticoagulant. Brooks an colleagues (2002) compare
anticoagulation in postpartum women with that o age-matche
nonpregnant controls. Te ormer require a signicantly larger
meian total ose o wararin—45 versus 24 mg—an a longer
time—7 versus 4 ays—to achieve the target INR.
Direct-acting Oral Anticoagulants
O these newer oral anticoagulants, abigatran (Praaxa)
inhibits thrombin an rivaroxaban (Xarelto) an apixaban
(Eliquis) inhibit actor Xa. Tese agents are becoming the
rugs o choice or nonpregnant subjects with thromboembolism (Kruger, 2019). Currently, very ew reports aress these
newer agents uring pregnancy an breasteeing, an thus the
human reprouctive risks are essentially unknown (Lameijer,
2018; Rosenbloom, 2019). Despite this, the GARFIELD-VE
stuy reporte that irect-acting oral anticoagulant use in pregnant women was gaining avor (Jerjes-Sanchez, 2021). Dabigatran crosses the placenta, however, it is unknown whether any
o these agents are excrete in breast milk (Bapat, 2014). At
this time, because o the potential or inant harm, a ecision
shoul be mae to either avoi breasteeing or use an alternative anticoagulant, such as wararin, in breasteeing women
(Bates, 2021; Kruger, 2019).
■ Complications of Anticoagulation
Tree signicant complications associate with anticoagulation
are hemorrhage, thrombocytopenia, an osteoporosis. Te latter two are unique to heparin, an their risk may be reuce
with LMWHs. Te most serious complication is hemorrhage,
which is more likely i there has been recent surgery or lacerations. roublesome bleeing is also more likely i the heparin
osage is excessive. Unortunately, management schemes using
laboratory testing to ientiy when a heparin osage is sufcient to inhibit urther thrombosis, yet not cause serious hemorrhage, have been iscouraging.
Heparin-induced Thrombocytopenia
Tere are two types—the most common is a nonimmune,
benign, reversible thrombocytopenia that evelops within
the rst ew ays o therapy an resolves in approximately 5
ays without therapy cessation. Te secon is the severe orm
o heparin-inuce thrombocytopenia, which results rom an
immune reaction involving IgG antiboies irecte against
complexes o platelet actor 4 an heparin. Te iagnosis o
heparin-inuce thrombocytopenia (HI) is base on a rop
in the platelet count o more than 50 percent or thrombosis
beginning 5 to 10 ays ater the start o heparin in association
with the appearance o platelet-activating HI antiboies. Te
all in platelet count in HI occurs rapily—over a perio o 1
to 3 ays—an is assesse relative to the highest platelet count
ater the start o heparin. Te typical nair is 40,000 to 80,000
platelets per microliter (Greinacher, 2015).
Although the incience o HI is approximately 3 to 5
percent in nonpregnant iniviuals, it is <0.1 percent in
obstetrical patients (American College o Obstetricians an
Gynecologists, 2020b). Fausett an coworkers (2001) reporte
no cases among 244 heparin-treate gravias compare with 10
among 244 nonpregnant patients. Accoringly, the American986
Section 12
Medical and Surgical Complications
College o Chest Physicians recommens against platelet count
monitoring when the risk o HI is consiere to be <1 percent (Linkins, 2012). In others, they suggest monitoring every
2 or 3 ays rom ay 4 until 14.
Women with a presumptive iagnosis o HI shoul have
laboratory testing or antiplatelet antiboies or by unctional
assays. However, these tests oten require several ays to return
results, so initial management shoul be irecte by clinical
nings. Heparin therapy is stoppe, an alternative anticoagulation initiate. LMWH may not be entirely sae because it
has some cross reactivity with UFH. Te American Society o
Hematology recommens use o onaparinux (Arixtra), which
is a pentasaccharie actor Xa inhibitor (Bates, 2018). Successul use in pregnancy has been reporte (De Carolis, 2015;
Elsaigh, 2015). Last, platelet transusions are avoie (Greinacher, 2015).
Heparin-induced Osteoporosis
Bone loss may evelop with long-term heparin aministration—usually 6 months or longer—an is more prevalent in
cigarette smokers. UFH can cause osteopenia, an this is less
likely with LMWHs. Women treate with any heparin shoul
be encourage to take an oral aily 1500-mg calcium supplement (Cunningham, 2005; Lockwoo, 2012).
■ Anticoagulation and Abortion
Te treatment o DV with heparin oes not preclue pregnancy termination by careul curettage. Ater the proucts are
remove without trauma to the reprouctive tract, ull-ose
heparin can be restarte in several hours.
■ Anticoagulation and Delivery
Te eects o heparin on bloo loss at elivery epen on several variables: (1) ose, route, an timing o aministration; (2)
number an epth o incisions an lacerations; (3) intensity o
postpartum myometrial contractions; an (4) presence o other
coagulation eects. Bloo loss shoul not be greatly increase
with vaginal elivery i there are no lacerations, an the uterus
promptly contracts. Unortunately, such ieal circumstances o
not always prevail. Tus, heparin therapy generally is stoppe
uring labor an elivery.
Te American College o Obstetricians an Gynecologists
(2020b) recommens restarting UFH or LMWH no sooner
than 4 to 6 hours ater vaginal elivery or 6 to 12 hours ater
cesarean elivery. From their review, Moriuchi an associates
(2019) oun that thromboprophylaxis starte within 24 hours
ater cesarean elivery was sae. At Parklan Hospital, we wait
at least 24 hours to restart therapeutic-ose heparin ater cesarean elivery or ater vaginal elivery with signicant lacerations.
SUPERFICIAL VENOUS THROMBOPHLEBITIS
Trombosis limite strictly to the supercial veins o the
saphenous system is typically associate with varicosities or as a
sequela o an inwelling intravenous catheter. It is treate with
analgesia, elastic support, heat, an rest. Supercial vein thrombosis raises the risk o DV our- to six-ol. In a metaanalysis
o nonpregnant patients with thrombophlebitis, 18 percent ha
a concomitant DV an 7 percent ha a pulmonary embolism (Di Minno, 2016). Although controversial, the American
Society o Hematology suggests LMWH therapy (Bates, 2018).
PULMONARY EMBOLISM
Although it causes approximately 10 percent o maternal
eaths, pulmonary embolism is relatively uncommon uring
pregnancy an the puerperium. Accoring to Marik an Plante
(2008), 70 percent o gravias presenting with a pulmonary
embolism have associate clinical evience o DV. An recall
that between 30 an 60 percent o women with a DV will
have a coexisting silent pulmonary embolism.
■ Clinical Presentation
In almost 2500 nonpregnant patients with a proven pulmonary
embolism, symptoms inclue yspnea in 82 percent, chest
pain in 49 percent, cough in 20 percent, syncope in 14 percent, an hemoptysis in 7 percent (Golhaber, 1999). Other
preominant clinical nings typically inclue tachypnea,
apprehension, an tachycaria. In some cases, an accentuate
pulmonic closure soun, rales, an/or riction rub is hear.
Right axis eviation an -wave inversion in the anterior
chest leas may be evient on the electrocariogram. In most
cases, chest raiography results are normal. In others, nonspecic nings may inclue atelectasis, an inltrate, cariomegaly,
or an eusion. Vascular markings in the lung region supplie
by the obstructe artery can be lost. Although most women
are hypoxemic, a normal arterial bloo gas analysis oes not
exclue pulmonary embolism. Approximately a thir o young
patients have PO2 values >80 mm Hg. Tus, the alveolar- arterial oxygen tension ierence is a more useul inicator o isease. More than 86 percent o patients with acute pulmonary
embolism will have an alveolar-arterial ierence >20 mm Hg
(Lockwoo, 2012). Even with massive pulmonary embolism,
signs, symptoms, an laboratory ata to support the iagnosis
may be eceptively nonspecic.
■ Massive and Submassive Pulmonary
Embolism
Dene as embolism causing hemoynamic instability, these
account or 5 to 10 percent o cases (Hanal-Örece, 2019).
Acute mechanical obstruction o the pulmonary vasculature
causes increase vascular resistance an pulmonary hypertension ollowe by acute right ventricular ilation. In otherwise
healthy patients, signicant pulmonary hypertension oes not
evelop until 60 to 75 percent o the pulmonary vascular tree
is occlue (Guyton, 1954). Moreover, circulatory collapse
requires 75- to 80-percent obstruction. Tis is epicte in
Figure 55-4 an emphasizes that most acutely symptomatic
emboli are large an likely a sale embolism (Singhal, 1973).
Tese are suspecte when the pulmonary artery pressure is substantively increase as estimate by echocariography.Thromboembolic Disorders 987
CHAPTER 55
Submassive embolism is iagnose when there is evience
o right ventricular ysunction (Hanal-Örece, 2019). Te
mortality rate approaches 25 percent, which compares with
a 1-percent rate without such ysunction (Kinane, 2008).
It is important in these cases to inuse crystallois careully
an to support bloo pressure with vasopressors. Aggressive
intravenous ui inusion has been associate with worsening right-sie ventricular ysunction (Konstanties, 2014).
As iscusse on page 988, oxygen treatment, tracheal intubation, an mechanical ventilation are complete preparatory to
thrombolysis, lter placement, or embolectomy.
■ Diagnosis
In most cases, recognition o a pulmonary embolism requires
a high inex o suspicion that prompts objective evaluation.
Exposure o the mother an etus to ionizing raiation is a concern when investigating a suspecte pulmonary embolism uring pregnancy. However, this concern is largely overrule by
the hazars o missing a potentially atal iagnosis. Moreover,
erroneously assigning a iagnosis o pulmonary embolism to a
pregnant woman is also raught with problems. It unnecessarily exposes the mother an etus to the risks o anticoagulation
treatment an will impact elivery plans, uture contraception, an thromboprophylaxis uring subsequent pregnancies.
Tereore, investigations shoul aim or iagnostic certainty
(Cohen, 2020).
Diagnosis o a pulmonary embolism ollows the same
algorithm as or DV shown in Figure 55-2. In aition to
compression ultrasoun o the extremities, i a pulmonary
embolism is suspecte, chest x-ray an electrocariogram may
be revealing. Echocariography is useul to etect other con-
itions that mimic pulmonary embolism—acute myocarial
inarction, pericarial tamponae, an aortic issection. Further imaging with compute tomography (C) scanning, MR
imaging, or ventilation-perusion lung scanning conrms the
iagnosis (American College o Obstetricians an Gynecologists, 2020b). As iscusse later (p. 988), the American Society o Hematology recommens lung scanning as the rst-line
iagnostic tool (Bates, 2018). At Parklan Hospital we preerentially use C-pulmonary angiography or suspecte pulmonary embolism.
Computed Tomographic Pulmonary Angiography
Multietector C-pulmonary angiography (CPA) is the most
commonly employe technique to iagnose pulmonary embolism in nonpregnant patients. Te technique is escribe urther in Chapter 49 (p. 874), an an imaging example is shown
in Figure 55-5. Te estimate etal raiation exposure averages
0.45 to 0.6 mGy. Te estimate maternal breast ose is 10 to
70 mGy (Waksmonski, 2014).
CPA has many avantages, but we n that the higher
resolution allows etection o previously inaccessible smaller
istal emboli that have uncertain clinical signicance. Similar
observations have been reporte by others (Anerson, 2007;
Hall, 2009). Bourjeily an colleagues (2012) perorme a
ollow-up stuy o 318 pregnant women who ha a negative
CPA perorme or a suspecte pulmonary embolism. All
Pulmonary trunk
Diameter = 3 cm; total area = 9 cm2
Segmental arteries (19)
Dia. 6 mm each;
total area = 36 cm2
Lobar arteries (5)
Dia. 8 mm each;
total area = 13 cm2
Subsegmental arteries (65)
Dia. 4 mm each;
total area = 817 cm2
Right and left pulmonary artery
Dia. 1.5 cm each; total area = 9 cm2
Left lobar arteries (2)
Right lobar arteries (3)
FIGURE 55-4 Schematic of pulmonary arterial circulation. Note that the cross-sectional area of the pulmonary trunk and the combined
pulmonary arteries is 9 cm. A large saddle embolism could occlude 50 to 90 percent of the pulmonary tree, causing hemodynamic instability. As the arteries give off distal branches, the total surface area rapidly increases, that is, 13 cm for the combined five lobar arteries,
36 cm for the combined 19 segmental arteries, and more than 800 cm for the total 65 subsegmental arterial branches. Thus, hemodynamic
instability is less likely with emboli past the lobar arteries.988
Section 12
Medical and Surgical Complications
were seen 3 months ollowing their initial presentation or at
6 weeks postpartum. None o these women were subsequently
iagnose with a thromboembolism.
Ventilation-Perfusion Scintigraphy Lung Scan
Tis technique involves a small ose o raiotracer such as
intravenously aministere technetium-99m macroaggregate
albumin. Tere is negligible etal an maternal breast raiation
exposure—0.1 to 0.4 mGy. Te scan may not provie a e-
nite iagnosis because many other conitions can cause perusion eects. Examples are pneumonia or local bronchospasm.
Chan an coworkers (2002) oun that a ourth o ventilationperusion scans in pregnant women were noniagnostic. In
these instances, CPA is preerre (romeur, 2017).
o compare the perormance o lung scintigraphy an
CPA, Revel an associates (2011) evaluate 137 pregnant
women with suspecte pulmonary embolism. Te two moalities perorme comparably an ha no signicant ierences
between the proportions o positive, negative, or ineterminate
results. Specically, the proportion o ineterminate results or
both approximate 20 percent, Similarly, one systematic review
conclue that both CPA an lung scintigraphy seem appropriate or exclusion o pulmonary embolism uring pregnancy
(van Mens, 2017).
Intravascular Pulmonary Angiography
Tis requires catheterization o the right sie o the heart an
is consiere the reerence test or pulmonary embolism. With
newer-generation multietector C scanners, however, the
role o invasive pulmonary angiography has been questione.
Tis is especially true given the higher raiation exposure or
the etus (Konstantinies, 2014). Other etractions are that it
can be time consuming, uncomortable, an associate with
ye-inuce allergy an renal ailure. It is reserve or conrmation when less invasive tests are equivocal.
■ Management
Immeiate treatment or pulmonary embolism is ull anticoagulation similar to that or DV as iscusse on page 982 an
shown in able 55-4. Tere are several complementary proce-
ures that may be inicate.
Vena Caval Filters
Te woman who has very recently suere a pulmonary embolism an who must unergo cesarean elivery presents a particularly serious problem. Reversal o anticoagulation may be
ollowe by another embolus, an surgery while ully anticoagulate requently results in lie-threatening hemorrhage or
troublesome hematomas. In these cases, placement o a vena
caval lter shoul be consiere beore surgery (Marik, 2008).
Moreover, in the very inrequent circumstances in which heparin therapy ails to prevent recurrent pulmonary embolism
rom the pelvis or legs or in which embolism evelops rom
these sites espite heparin treatment, a vena caval lter may also
be inicate. Such lters can also be use ollowing massive
emboli in patients who are not caniates or thrombolysis.
Te evice is inserte through either the jugular or emoral
vein an can be inserte uring labor (Jamjute, 2006). Routine
lter placement has no ae avantage to heparin given alone
(Decousus, 1998). Retrievable lters may be use as short-term
protection an then remove 1 to 2 weeks later (Liu, 2012).
From their systematic review, Harris an colleagues (2016)
oun that complication rates in pregnant women with vena
caval lters are comparable to those in nonpregnant patients.
In another series o 24 lters place in obstetrical patients, 29
percent ha complications incluing removal ailure (Rottenstreich, 2019).
Thrombolysis
Compare with heparin, thrombolytic agents provie more
rapi lysis o pulmonary clots an improvement o pulmonary
hypertension in lie-threatening cases (Bates, 2021; Golhaber, 2018). In one stuy o nonpregnant patients receiving
heparin or an acute submassive pulmonary embolism, those
receiving the recombinant tissue plasminogen activator alteplase
ha a lower risk o eath or treatment escalation (Konstantinies, 2002). One metaanalysis o trials involving nonpregnant patients reporte that the risk o recurrence or eath was
signicantly lower in patients given thrombolytic agents an
heparin compare with those given heparin alone—10 versus
17 percent (Agnelli, 2002). Importantly, however, there were
ve—2 percent—atal bleeing episoes in the thrombolysis
group an none in the heparin-only group.
Tere have been several case reports an reviews o thrombolysis in pregnant women. Leonhart an coworkers (2006)
ientie 28 reports o tissue plasminogen activator use uring pregnancy. en cases were or thromboembolism. Complication rates were similar to those in nonpregnant patients,
an the authors conclue that such therapy shoul not be
withhel uring pregnancy i inicate. Akazawa an Nishia
FIGURE 55-5 Axial image of the chest from a four-channel multidetector spiral computed tomographic scan performed after
administration of intravenous contrast. There is enhancement of
the pulmonary artery with a large thrombus on the right (arrow)
consistent with pulmonary embolism. (Reproduced with permission from Dr. Michael Landay.)Thromboembolic Disorders 989
CHAPTER 55
(2017) reviewe 13 cases o systemic thrombolytic therapy
aministere uring the rst 48 hours ater elivery. Bloo
transusion was require in ve o the eight cesarean eliveries,
incluing three cases o hysterectomy an two cases o hematoma rainage. Sousa-Gomes an associates (2019) reviewe
outcomes in 141 pregnant women unergoing thrombolysis
or VE or stroke. Maternal eath complicate 3 percent o
cases, an major bleeing occurre in 9 percent.
Embolectomy
Given the efcacy o thrombolysis an lters, surgical embolectomy is uncommonly inicate. Publishe experience with
emergency embolectomy uring pregnancy is limite to case
reports (Colombier, 2015; Saee, 2014). From their review,
Ahearn an colleagues (2002) oun that although the operative risk to the mother is reasonable, the stillbirth rate is 20 to
40 percent.
THROMBOPROPHYLAXIS
A Cochrane review o guielines or thromboprophylaxis in
pregnancy conclue that there is a lack o overall agreement
about which women shoul be oere thromboprophylaxis
(Mileton, 2021). Te American Society o Hematology summarize that evience-base recommenations rely largely on
observational stuies an on ata extrapolate rom nonpregnant patients. In many cases, this le them to suggest—rather
than recommend—various schemes or thromboprophylaxis
(Bates, 2018). In an earlier stuy, Cleary-Golman an
coworkers (2007) surveye 151 ellows o the American College o Obstetricians an Gynecologists an reporte that intervention without a clear inication is common. able 55-5 lists
several consensus recommenations or thromboprophylaxis.
In some cases, more than one option is liste, thus illustrating
the conusion that currently reigns. It is important to emphasize that the ecision to treat with anticoagulation in pregnancy
is inuence by personal VE history, amily history o VE,
severity o thrombophilias, an aitional risk actors such as
obesity, cesarean elivery, or prolonge immobility (American
College o Obstetricians an Gynecologists, 2020a).
■ Prior Venous Thromboembolism
In general, either antepartum surveillance or heparin prophylaxis is recommene or women with prior VE but without a
recurrent risk actor. engborn an associates (1989), however,
suggeste that such management may not be eective. Tey
reporte outcomes in 87 pregnant Sweish women who ha
prior thromboembolic isease an were not teste or thrombophilias. Despite unractionate heparin prophylaxis, which
was usually 5000 U twice aily, 15 percent evelope antepartum VE recurrence. Tis compare with 12 percent not
given heparin.
Brill-Ewars an colleagues (2000) prospectively stuie
125 pregnant women with a single prior VE. Antepartum
heparin was not given, but anticoagulant therapy was given or
4 to 6 weeks postpartum. Six women ha a recurrent venous
thrombosis, but there were no recurrences in women without
a known thrombophilia or whose prior thrombosis was associate with a temporary risk actor. A stuy o 88 women
without antiphospholipi antiboies an who were not given
antithrombotic prophylaxis reporte a subsequent pregnancyor puerperium-relate VE in 22 percent (De Steano, 2006).
O 20 women whose original thrombosis was associate with a
transient risk actor—not incluing pregnancy or oral contraceptive use—there were no recurrences uring pregnancy, but
two uring the puerperium. Tese nings imply that women
with a prior thrombosis in association with a thrombophilia or
in the absence o a temporary risk actor generally shoul be
given both antepartum an postpartum prophylaxis (Connors,
2017). Tese ata also suggest that or women with a prior
VE, antithrombotic prophylaxis uring pregnancy coul be
tailore accoring to the circumstances o the original event.
It is important to emphasize that VTE may recur despite antithrombotic prophylaxis. A stuy o 270 women who ha at least
one previous VE oun that 10 percent suere a recurrent
VE (Galambosi, 2014). welve o these recurrences occurre
early in pregnancy beore the initiation o antithrombotic prophylaxis, an 16 occurre espite prophylactic use o LMWH.
Our practice at Parklan Hospital or many years or
women with a history o prior VE was to aminister subcutaneous UFH, 5000 to 7500 units two to three times aily. More
recently, we have use 40 mg o enoxaparin given subcutaneously aily with transition to UFH near elivery. With either
regimen, the recurrence o ocumente DV embolization has
been uncommon.
■ Cesarean Delivery
Te risk or DV an especially or atal thromboembolism
rises many ol ollowing cesarean elivery compare with
that ater vaginal elivery. When consiering that a thir o
women giving birth in the Unite States yearly unergo cesarean elivery, pulmonary embolism is unerstanably a major
cause o maternal mortality (Creanga, 2017; Petersen, 2019).
Tat sai, the lack o consensus escribe earlier by Mileton an coworkers (2021) creates consierable variation in the
current recommenations promulgate by the American College o Obstetricians an Gynecologists, the Royal College o
Obstetricians an Gynaecologists, an the American College o
Chest Physicians (Palmerola, 2016).
Aherence to iniviual society guielines ollowing cesarean elivery coners a greater risk in some instances. Accoring
to the Society or Maternal-Fetal Meicine (2020), i American College guielines were ollowe, only 1 percent o these
women woul be caniates or thromboprophylaxis. Almost
85 percent o the same cohort woul be given thromboprophylaxis ollowing Royal College guielines an about 35 percent i
American College o Chest Physician guielines were ollowe.
Some comparisons o these thromboprophylaxis guielines are
shown in Table 55-6.
Since 2011, the American College o Obstetricians an
Gynecologists (2020b) recommens placement o pneumatic
compression evices beore cesarean elivery or all women not
alreay receiving thromboprophylaxis. Tis recommenation was
base primarily on consensus an expert opinion. For patients990
Section 12
Medical and Surgical Complications
unergoing cesarean elivery with aitional risk actors or
thromboembolism, both pneumatic compression evices an
UFH or LMWH may be recommene. Te College stipulate
that cesarean elivery in an emergency setting shoul not be elaye because o the time necessary to begin thromboprophylaxis.
Implementation o this strategy by the Hospital Corporation
o America, the largest or-prot obstetrical health care elivery
system in the Unite States, was associate with a reuction in
eaths rom pulmonary embolism rom 7 o 458,097 cesarean
births to 1 o 465,880 cesarean births (Clark, 2011, 2014).
In 2016, the National Partnership or Maternal Saety publishe several consensus recommenations or the prevention
o maternal VE (D’Alton, 2016). Tese recommenations
inclue expane use o antenatal thromboprophylaxis or
women hospitalize 3 ays or longer, expane use o prophylaxis uring an ater vaginal elivery, an expane use
o pharmacological prophylaxis to most women ater cesarean
elivery. In response, Sibai an Rouse (2016) expresse concern that these new recommenations erive rom sparse ata
o questionable applicability to obstetrical patients. Tey calle
or better quality evience to measure the benets, harms, an
costs o increase pharmacological thromboprophylaxis. As
aptly expresse by Macones (2017), “an intervention, such
as increase postcesarean pharmacologic thromboprophylaxis,
where there are legitimate concerns about efcacy an saety,
requires a much higher egree o evience beore a national
guieline is implemente.” We agree with these sentiments.
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