Pregnancy and its outcome in women with and without surgical treatment of congenital heart disease.. Percutaneous mitral balloon valvotomy during pregnancy in a patient with severe mitra
Trang 175 Prifti E , Crucean A , Bonacchi M Early and long term outcome of the arterial switch operation for transposition of the great arteries:
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Trang 4Chapter 20
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Trang 5Critical Care Obstetrics, 5th edition Edited by M Belfort, G Saade,
M Foley, J Phelan and G Dildy © 2010 Blackwell Publishing Ltd
Donna Dizon - Townson
Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake City, UT and Intermountain
Healthcare, Department of Maternal - Fetal Medicine, Provo, UT, USA
Pulmonary embolism (PE), albeit a rare event, remains the
leading cause of maternal mortality in the United States [1,2]
Furthermore, deep venous thrombosis (DVT) can cause signifi
-cant morbidity [3] Pregnancy - related venous thromboembolism
(VTE) has been reported to occur in approximately 0.5 – 3.0 per
1000 pregnancies based on studies using radiographic
documen-tation [4 – 6] Clinical symptomatology should be confi rmed with
objective testing Almost 75% of patients who present with
sus-pected thromboembolic disease, and are then subjected to testing
such as Doppler ultrasound or venography, are found not to have
the condition [7] When DVT is diagnosed and heparin
treat-ment instituted, the incidence of PE and maternal mortality can
be decreased by threefold and 18 - fold, respectively The goal of
this review is to facilitate the recognition of the clinical signs and
symptoms of VTE disorders, describe a rational approach to the
work - up of a suspected hypercoagulable state, and review the use
of various diagnostic and treatment modalities
Incidence and r isk f actors
Although many studies about maternal mortality cite PE as the
leading cause, they do not distinguish VTE from amniotic fl uid
or air embolism [8 – 10] At least half of these deaths are due to
thrombotic embolism [9,11 – 15] During 1991 – 1999, a total of
4200 deaths were determined to be pregnancy related The overall
pregnancy - related mortality ratio was 11.8 deaths per 100,000 live
births and ranged from 10.3 in 1991 to 13.2 in 1999 The leading
causes of pregnancy - related death were embolism (20%),
hemor-rhage (17%), and pregnancy - induced hypertension (16%) The
leading causes of death among women who died after a live birth
(60% of all pregnancy - related deaths) were embolism (21%),
pregnancy - induced hypertension (19%), and other medical
con-ditions (17%) 2 (Table 21.1 )
As illustrated in Figure 21.1 , from 1970 to 1985, maternal mortality rates from PE declined by 50% [9] The traditionally held view is that the maternal risk for VTE is greater in the imme-diate puerperium, especially following cesarean delivery Postpartum DVT has been reported to occur 3 – 5 times more often than antepartum DVT, and 3 – 16 times more frequently after cesarean as opposed to vaginal delivery [16,17] In contrast, Rutherford and associates found that the highest incidence of pregnancy - related VTE was not in the puerperium but in the fi rst trimester of pregnancy [18,19] (Figure 21.2 ) These authors also found that the risk of DVT did not increase with advancing ges-tational age but stayed relatively constant (see Figure 21.2 ) In contrast, PE (Figure 21.3 ) was almost twice as likely to occur in the postpartum patient and appeared to be related to the route
of delivery More recently, Gerhardt and colleagues reported on
119 women with a pregnancy - related VTE [20] Approximately half (62 women) experienced a DVT during pregnancy: 14 (23%)
in the fi rst trimester, 13 (21%) in the second trimester, and 35 (56%) in the third trimester The other half (57 women) experi-enced a DVT in the immediate puerperium: 38 (68%) following vaginal delivery and 19 (32%) following cesarean section In summary, pregnancy - related VTE may occur at any time during pregnancy or the immediate puerperium A recent 30 - year pop-ulation - based study of trends in the incidence of VTE during pregnancy and post partum confi rmed the signifi cant riks of VTE during the puerperium [21] Although the incidence of PE has decreased over time, the incidence of DVT is unchanged Therefore, regardless of gestational age, the clinician should have
a heightened awareness for the diagnosis when a gravid or post-partum woman presents with clinical symptomatology suspicious for VTE
Important risk factors for VTE during pregnancy are immobil-ity and bed rest “ Bed rest ” is often recommended for a variety
of obstetric disease such as threatened preterm labor or pre eclampsia The clinician should keep in mind the increased risk for VTE when making recommendations for limited maternal physical activity or long distance travel Traveling long distances
by air may also increase a pregnant woman ’ s risk of a PE
Trang 6Chapter 21
Additional risk factors in the gravid woman include surgery,
trauma or a prior history of superfi cial vein thrombosis [22]
Ethnic background and maternal age are important risk factors
for PE The overall mortality rate for black women was 3.2 times
higher than for white women In addition, women 40 years or
older were at a 10 times greater risk of mortality than women
under 25 for both ethnic groups [9] (Figure 21.4 ) Recent
preg-nancy surveillance has confi rmed that pregpreg-nancy - related
mortal-ity ratios continued to be 3 – 4 times higher for black women than
7
6
5
4
3
2
1
0
Date
Figure 21.1 Maternal deaths due to pulmonary embolism per 100,000 births
from 1970 to 1985 (Reproduced by permission from Franks AL, Atrash AK,
Lawson, et al Obstetrical pulmonary embolism mortality United States
1970 – 1985 Am J Publ Health 1990; 80: 720 – 722.)
70 60 50 40 30 20 10
0
Trimester
Figure 21.2 Distribution of deep venous thrombosis and pulmonary embolism
during each trimester of pregnancy: an 11 - year review (Reproduced by permission from Rutherford SE, Montoro M, McGehee W, et al Thromboembolic disease associated with pregnancy: an 11 - year review, SPO Abstract 139 Am J Obstet Gynecol 1991; 164: 286.)
Table 21.1 Causes of pregnancy - related death, by outcome of pregnancy and pregnancy - related mortality ratios ( PRMR * ) United States, 1991 – 1999
Cause of death Outcome of pregnancy (% distribution) All outcomes
Live birth Stillbirth Ectopic Abortion †
Molar Undelivered Unknown % PRMR (n = 2519) (n = 275) (n = 237) (n = 165) (n = 14) (n = 438) (n = 552) (n = 4200)
Total † † 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 11.8
* Pregnancy - related deaths per 100 000 live births
† Includes spontaneous and induced abortions
§ Pregnancy - induced hypertension
¶ Cerebrovascular accident
* * The majority of the other medical conditions were cardiovascular, pulmonary, and neurologic problems
† †
Percentages might not add to 100.0 because of rounding
Reproduced by permission from Chang J, Elam - Evans LD, Berg CJ, et al Pregnancy - related mortality surveillance – United States 1991 – 1999 MMWR 2003; 52(SSO2):
1 – 8
Trang 7(unprovoked) had an antepartum recurrence rate of 5.9% (95%
CI 1.2 – 16%) It is assumed that the risk of recurrence diminishes
as the time from initial event increases The mean time from initial event to enrollment in the study was 4 years In another study, on a cohort of 1104 women with previous VTE, 88 of them became pregnant and did not receive thromboprophylaxis There were nine recurrences during pregnancy and 10 during the puer-perium, with a rate of 5.8% (95% CI 3.0 – 10.6) In pregnancy, the recurrence rate was 7.5% (95% CI 4.0 – 13.7) if the fi rst VTE was unprovoked, related to pregnancy or to oral contraceptive use, whereas no recurrence occurred if the fi rst VTE related to other transient risk factors [25]
Inherited and acquired thrombophilias are additional risk factors for VTE The inherited thrombophilias include defi cien-cies of protein C, protein S, and antithrombin III, factor V Leiden, prothrombin G20210A, and the 5,10 - methylenetetrahydrofolate reductase mutations The most commonly investigated acquired thrombophilia is the antiphospholipid syndrome
In summary, the risk of VTE varies among pregnant women, therefore individualization of management must be emphasized This risk will depend not only on the pregnancy, but also on additional clinical factors such as a prior history of thromboem-bolism, mode of delivery, prolonged immobilization, age, and ethnicity (Table 21.2 ) In the presence of a personal or familial history of VTE, testing for thrombophilia should be accom-plished to better defi ne the specifi c risk A comprehensive throm-bophilia work - up should include testing for functional defi ciencies
of protein C, protein S, and antithrombin III These tests should
be performed preferably when the patient is not pregnant and prior to anticoagulation In addition, molecular tests for factor V Leiden and the prothrombin G20210A mutation, which are unaf-fected by pregnancy or anticoagulation, should also be performed
To complete the evaluation, screening for antiphospholipid syn-drome with testing for IgG and IgM anticardiolipin antibodies and lupus anticoagulant should be included A positive test for antiphospholipid syndrome appears to carry the greatest impact
on maternal and fetal outcome in subsequent pregnancies
Normal h emostasis
Few systems are more complex than hemostasis Interactions among the vessel wall, platelets, and soluble molecules in the
for white women [2] In addition, the pregnancy - related
mortal-ity ratios for black women aged > 39 years were particularly high
in comparison with white women in the same age group [2]
Blood groups A and AB may be associated with an increased risk
for VTE during pregnancy [23]
A prior history of a VTE confers a greater risk for recurrence
especially if the initial event was idiopathic or associated with a
hereditary or acquired thrombophilia [24] In a prospective
cohort study investigating the risk of recurrence of pregnancy
related VTE in 125 women who had a history of VTE, heparin
was withheld antepartum but administered 6 weeks postpartum
in all women The antepartum recurrence rate was 2.4% (95% CI
0.2 – 6.9%) There were no recurrences in the 44 patients (0%:
95% CI 0.0 – 8.0%) who did not have thrombophilia and had a
previous episode of thrombosis that was associated with a
tem-porary risk factor Patients with a positive result for
thrombo-philia and/or a previous episode of thrombosis that was idiopathic
Deep venous thrombosis Pulmonary embolism
0
10
20
30
40
50
60
70
80
90
100
Cesarean section Vaginal delivery
Figure 21.3 The frequency of postpartum deep venous thrombosis and
pulmonary embolism according to route of delivery (Reproduced by permission
from Rutherford SE, Montoro M, McGehee W, et al Thromboembolic disease
associated with pregnancy: an 11 - year review Am J Obstet Gynecol
1991;164:286.)
20–24
White
Black
* Deaths per 100,000 live births
0
20
40
60
80
100
120
140
160
180
Age group (yrs)
Figure 21.4 Pregnancy - related mortality ration, by age and race – United
States, 1991 – 1999 (Reproduced by permission from Chang J, Elam - Evans LD,
Berg CJ, et al Pregnancy - related mortality surveillance – United States
1991 – 1999 MMWR 2003; 52(SSO2): 1 – 8.)
Table 21.2 Factors associated with a higher risk of pulmonary embolism
Maternal age Ethnic background Operative delivery Prior thromboembolism Prolonged immobilization Inherited/acquired coagulation disorders Trauma
Trang 8Chapter 21
The intrinsic and extrinsic pathways lead to the fi nal common clotting pathway Both pathways are activated by components of the vessel wall and lead to activation of progressive exponential increase in subsequent factors In the intrinsic pathway, high molecular weight kininogen and kallikrein are cofactors for the initial step of the process, the activation of factor XII (XIIa) By catalyzing the formation of kallikrein from prekallikreins, factor XIIa also helps to initiate fi brinolysis, activate the complement system, and produce kinins [26] Factor XI is activated by XIIa and then cleaves factor IX to form IXa In comparison, the extrin-sic pathway is so named because this pathway relies on tissue thromboplastin as a cofactor Tissue thromboplastin is released into the circulation following membrane damage or proteolysis [26] Factor VII is then activated to VIIa which, with tissue thromboplastin, can activate factors IX or X The common pathway begins with activation of factor X by either VIIa or IXa,
in combination with the protein cofactor VIII:C (the antihemo-philic factor) and the calcium ion, on the platelet surface (to form
PF 3 ) Factor Xa, assisted by cofactor Va, enzymatically divides prothrombin into thrombin and a peptide activation fragment,
F 1 + 2 Separation from this fragment liberates thrombin into the
fl uid phase Thrombin catalyzes the formation of fi brin mono-mers from fi brinogen and, thus, releases fi brinopeptides A and B and facilitates activation of V, VIII:C, and XIII A fi brin gel is created by the hydrophobic and electrostatic interactions of the
fi brin α and γ chains Subsequently, factor XIIIa forms covalent bonds linking nearby α and γ chains to form a stable polymerized
fi brin clot into which water is also incorporated
Trapped within the clot are proteins that contribute to the enzymatic digestion of the fi brin matrix: plasminogen and minogen activators A variety of substances can activate plas-minogen Plasma plasminogen activator is activated by factor XIIa Release of tissue activators (tissue plasminogen activator) from blood vessel epithelium (especially venous) is stimulated by exercise, emotional stress, trauma, surgery, hypotensive shock, pharmacologic agents, and activated protein C [17,26,31] The
fi brinolytic enzymes streptokinase and urokinase also activate plasminogen [32] Having been activated from plasminogen, plasmin cleaves arginyl - lysine bonds in many substrates, includ-ing fi brogen, fi brin, factor VIII, and complement [32,33] The result of plasmin action on fi brin and fi brinogen is release of protein fragments, referred to as fi brinogen degradation products (or fi brin split products) The larger fragments, which may have slow clotting activity, are further divided by plasmin These frag-ments have anticoagulant activity, in that they inhibit the forma-tion and cross - linking of fi brin [26] Measurement of fi brin degradation products provides an indirect measurement of fi bri-nolysis α 2 antiplasmin, a specifi c plasmin inhibitor that binds to
fi brin and fi brinogen, is found in serum, platelets, and within the clot, along with other inhibitors of plasmin or plasminogen activity [32]
As a potent inhibitor of thrombin, antithrombin III (AT III)
is important in the regulation of hemostasis In decreasing affi n-ity, AT III binds and inactivates factors IXa, Xa, XIa, and XIIa
vicinity of an injury work to repair the vessel defect without
sacrifi cing nearby vessel patency The key processes are: (i)
vasoconstriction; (ii) formation of a platelet plug; (iii) formation
of a stable “ seal ” by coagulation factors; (iv) prevention of
spread of the clot along the vessel wall; (v) prevention of
occlusion of the vessel by clots when possible; and (vi)
remodel-ing and gradual degradation of the clot after it is no longer
needed
The maintenance of normal blood fl ow requires intact, patent
blood vessels After an injury, the hemostatic and fi brinolytic
systems work together to protect vascular integrity and assist in
repair Vessel wall integrity, platelet aggregation, normal function
of the coagulation cascade, and fi brinolysis are all vital to this
process The initial response to injury is vasoconstriction, which
reduces local blood fl ow and limits the size of the defect that the
thrombus is required to seal [26] After platelets begin to adhere
to the exposed vessel wall, they change shape and secrete the
contents of their granules This action leads to further platelet
accumulation or aggregation, and results in the formation of a
platelet plug
The numerous substances released by platelets include
throm-boxane A 2 (TxA 2 ), a potent vasoconstrictor and preaggregatory
agent [27,28] ; serotonin, a vasoconstrictor [28] ; and adenosine
diphosphate (ADP), which enhances platelet aggregation
Platelets also produce vascular permeability factor and platelet
growth factor, which stimulate fi broblasts and vascular smooth
muscles [17,26] Released platelet factor 4 (PF 4) and β
thromboglobulin are used as markers of platelet activity [29,30]
The platelet contractile protein, thrombasthenin, enables
secre-tion of these substances and also enhances clot retracsecre-tion [17] A
platelet surface phospholipoprotein, platelet factor 3 (PF 3 ),
becomes available to bind factor V to catalyze the formation of
thrombin Thrombin, in turn, potentiates platelet aggregation
[30]
Whereas TxA 2 is the result of platelet arachidonic acid
metabo-lism, arachidonic acid in endothelial cells is metabolized to
pros-tacyclin (PGI 2 ) Prostacyclin inhibits aggregation and stimulates
vasodilation, and thus counteracts TxA 2 by increasing cyclic
ade-nosine monophosphate (AMP) [26] Because PGI 2 is
concen-trated within the vessel wall, the greater the distance from the
lumen, the lower the concentration of PGI 2 and the higher the
concentration of proaggregatory substances As platelets begin to
seal a vascular defect, the coagulation cascade produces fi brin,
which is polymerized as clot and incorporated into the platelet
plug
Proteolytic cleavage or conformational changes activate the
circulating clotting factors at the site of injury Factors II, VII, IX,
and X require a vitamin K - dependent reaction in the liver in
which γ - carboxyglutamic acid residues are attached to the protein
structure This action provides a location to form a complex with
calcium ion and phospholipid receptors on the platelet or
endo-thelial cell membranes Subsequent steps in the clotting cascade
occur at those sites and include the formation of thrombin Once
formed, this is released into the fl uid phase
Trang 9suggest ongoing increased fi brinolytic activity [40] Within an hour of delivery, this fi brinolytic potential decreases, as a result
of placental inhibitors [41] , and returns to normal These changes are believed to contribute to the hypercoagulability of the puer-perium [18,19] Levels of factors XI and XIII decrease When the placenta separates, tissue thromboplastin is released into the cir-culation, increasing the chance for thrombosis [42] Additional factors balancing the increased tendency toward coagulation may
be a pregnancy - specifi c protein (PAPP - A) which, like heparin, facilitates neutralization of thrombin by AT III [34] Platelet counts appear to remain in the normal range during pregnancy, but have been documented to be signifi cantly higher than prede-livery on days 8 and 12 after vaginal deprede-livery, and continued to rise 16 days after a cesarean delivery [43] The platelet count remained signifi cantly higher than predelivery values for 24 days after cesarean delivery [43]
Thrombophilias
Approximately half of the women who have a pregnancy - related VTE possess an underlying congenital or acquired thrombophilia [44] In almost 50% of patients with a hereditary thrombophilia, the initial thrombotic event occurs in the presence of an addi-tional risk factor such as pregnancy, oral contraceptive use, orthopedic trauma, immobilization or surgery [45,46]
Antithrombin III defi ciency, although the most rare of the congenital thrombophilias, is the most thrombogenic conferring
a 50% lifetime and pregnancy - related risk for thrombosis [47]
AT III defi ciency occurs in approximately 0.02 – 0.17% of the general population and 1.1% of individuals with a history of VTE Defi ciencies of protein C and protein S, although less thrombo-genic than AT III defi ciency, are more common [47] Carrier rates for defi ciencies of protein C and S are 0.14 – 0.5% in the general population In individuals who have had a history of VTE, 3.2% will have either protein C or protein S defi ciency
As a result of the Human Genome Project and major advances
in gene identifi cation, common genetic predispositions to thrombophilia, including factor V Leiden and the prothrombin G20210A mutation, have been described Resistance to APC is now known to be the most common genetic predisposition to
AT III acts as a substrate for these serine proteases but forms
stable intermediate bonds with the active portion and, thus,
neu-tralizes the respective enzyme [34] Heparin binds to AT III and
induces a conformational change that increases the affi nity of AT
III for thrombin The otherwise slow inactivation of thrombin by
AT III is accelerated greatly by even small amounts of heparin
After a stable thrombin – AT III complex is formed, heparin is
released and available for repetitive catalysis Excess amounts of
AT III are normally present in the circulation, and some are
bound to endothelial cell membranes via heparan, a sulfated
mucopolysaccharide with a function similar to heparin The
pres-ence of heparan on intact endothelial cell surfaces and its binding
to AT III, which neutralizes thrombin, help to prevent local
extension of the thrombus beyond the sites of vessel injury [35]
Defi ciency of AT III leads to a substantially higher incidence of
thrombotic events [36]
Proteins C and S are normally part of the protein C
anticoagu-lant system Like certain clotting factors, their synthesis depends
on vitamin K and involves addition of γ - carboxyglutamic acid
residues that enable binding, via calcium ions, to cell surfaces
Protein C is attached to endothelial cells, and protein S is attached
to endothelial and platelet membranes Endothelial cell surfaces
also have a specifi c protein receptor for thrombin –
thrombo-modulin The binding of thrombin to thrombomodulin, in the
presence of protein S, activates protein C (APC) and promotes
anticoagulation Complexes of APC and adjacently bound protein
S cofactor proteolyze the phospholipid - bound factors VIII:Ca
and Va This action results in a second mechanism to prevent
extension of the thrombus beyond the area of vessel injury [35]
Defi ciencies of either protein C or S are associated with an
increase in thromboembolic events [35,37] Homozygosity of
protein C defi ciency leads to fatal neonatal purpura fulminans
[38]
Changes in h emostasis in p regnancy
A century ago, Virchow described the triad of blood
hypercoagu-lability, venous stasis, and vascular damage conferring an
increased risk for thrombosis All these conditions occur during
pregnancy, thus conferring an increased risk for pregnancy
related VTE (Table 21.3 ) Estrogen stimulation of hepatic
synthe-sis of several procoagulant proteins increases with pregnancy
Levels of factors V, VII, VIII, IX, X, XII, and fi brinogen increase
muscle vascular relaxation and mechanical compression by the
gravid uterus occurs Placental separation and operative delivery
can cause endothelial vascular damage
Compensatory mechanisms such as concomitant rise in fi
bri-nolytic activity help to maintain coagulation equilibrium [39] As
pregnancy progresses, a low - grade chronic intravascular
coagula-tion results in fi brin deposicoagula-tion in the internal elastic lamina and
smooth muscle cells of the spiral arteries of the placental bed [40]
Increased fi brin split products and d - dimers during this period
Table 21.3 Hemostatic changes during pregnancy
Hemostatic changes promoting thrombosis Increased levels of factor V, VII, VIII, IX, X, XII, fi brinogen Placental inhibitors of fi brinolysis
Tissue thromboplastin released into the circulation at placental separation Venous stasis of the lower extremities
Endothelial damage associated with parturition Hemostatic changes countering thrombosis Decreased levels of factor XI, XIII Pregnancy - specifi c protein neutralizing AT III
Trang 10Chapter 21
of 104 women with a median postthrombosis interval of 11 years revealed that 4% had ulceration, and only 22% were without complaints [57] Finally, it is important to remember that preg-nant patients commonly complain of swelling and leg discomfort and, as such, do not require objective testing in every instance It
is important to remember that the fi rst sign of DVT may be the occurrence of a PE In a similar manner, silent DVT has been found in 70% of patients with angiographically proven PE [58] During the initial evaluation in a pregnant patient with clinical symptomatology suspicious for a pregnancy - related VTE, risk factors as described above should be sought Again “ bed rest ” or limited physical activity, which is frequently recommended for a variety of obstetric diseases, is a common risk factor for VTE events
Diagnostic s tudies
Ultrasound
Non - invasive testing is usually the fi rst step in confi rming the diagnosis of DVT Real - time imaging with compression ultra-sound (CUS), including duplex Doppler, is the method of choice CUS uses fi rm compression with the ultrasound transducer probe
to detect an intraluminal defect Experience is required for accu-rate interpretation, and the affected leg should be compared with the unaffected one Maneuvers such as Valsalva (which distends the vein and slows proximal fl ow), release of pressure over a distal vein (which causes a rapid proximal fl ow of blood), and squeez-ing of the muscles all cause changes in Doppler shift Real - time imaging in the presence of DVT may detect a mass in the vessel lumen, a failure of the lumen diameter to increase with Valsalva
Alternatively, imaging may identify a hematoma, popliteal cyst or other pathology to explain the patient ’ s symptoms In a symp-tomatic non - pregnant individual, CUS has a sensitivity of 95% for proximal DVT (73% for distal DVT) and specifi city of 96% for detecting all DVT, with a negative predictive value of 98% and
a positive predictive value for 97% in the non - pregnant symp-tomatic patient [60] At least 50% of small calf thrombi are missed due to collateral venous channels [61,62] Repeating the examination within 2 – 3 days may reveal a previously latent clot During pregnancy, the iliac vessels are especially diffi cult to image This is due to pressure from the gravid uterus on the inferior vena cava As a result, Doppler fi ndings must be inter-preted cautiously In the puerperal patient, imaging may visualize
thrombosis [48 – 50] Eighty to 100% of cases of resistance to APC
are due to the factor V Leiden mutation This is a missense
muta-tion in the gene encoding factor V protein Individuals with factor
V Leiden have normal levels of factor V protein, but this protein
is resistant to the normal degradation by APC The abnormal
factor V protein fails to undergo the normal conformation change
required for the proteolytic degradation by APC Heterozygous
carriers have a sevenfold increase in the risk for venous
throm-bosis, whereas homozygous carriers have an 80 - fold increased
risk Carrier rates for factor V Leiden are 6 – 8% in northern
Europeans and 4 – 6% in US Caucasians [51,52] In the largest
prospective observational study, 134 heterozygous carriers for the
FVL mutation were identifi ed among 4885 gravidas (2.7%) with
both FVL mutation status and pregnancy outcomes available No
thromboembolic events occurred among the FVL mutation
car-riers (0%, 95% CI 2.7%) Three pulmonary emoboli and one
deep venous thrombosis occurred (0.08%, 95% CI 0.02 – 0.21%),
all in FVL non - carriers Thus, although the FVL is a rather
common mutation in the Caucasian population, the relative risk
of a pregnancy - related thromboembolic event in a heterozygote
carrier is low [53] Another mutation in the 3 ′ untranslated
region of the prothrombin gene, prothrombin G20210A, leads to
elevated prothrombin levels ( > 155%) and a 2.1 - fold increase in
the risk for thrombosis The prevalence of the mutation in the
Caucasian population is 2% The prevalence of the mutation is
6% among unselected patients with thrombosis and about 18%
in families with unexplained thrombophilia
Deep v enous t hrombosis
Clinical d iagnosis
In the gravid patient, DVT appears to occur more often in the
deep proximal veins and has a predilection for the left leg
[15,54,55] The clinical diagnosis of DVT [56] is diffi cult and
requires objective testing Of those patients with clinically
sus-pected DVT, half will not be confi rmed by objective testing Due
to the long - term implications of anticoagulant therapy and the
expense of a hypercoagulable work - up, clinical symptomatology
of VTE should usually be confi rmed with objective testing before
a diagnosis is rendered
Symptoms and signs of DVT are illustrated in Table 21.4
Swelling is considered whenever there is at least a 2 cm measured
difference in circumference between the affected and normal
limbs Homan ’ s sign is present when passive dorsifl exion of the
foot in a relaxed leg leads to pain, presumably in the calf or
pop-liteal areas The Lowenberg test is positive if pain occurs distal to
a BP cuff rapidly infl ated to 180 mmHg The presence of marked
swelling, cyanosis or paleness, a cold extremity or diminished
pulses signals the rare obstructive iliofemoral vein thrombosis
DVT has also signifi cant long - term implications, and a prior
history of DVT may affect the patient ’ s symptomatology Years
after a severe obstructive DVT, patients may experience
postphle-bitic syndrome (skin stasis dermatitis or ulcers) An investigation
Table 21.4 Clinical symptoms and signs of lower extremity deep
venous thrombosis
Unilateral pain, swelling, tenderness, and/or edema Limb color changes
Palpable cord Positive Homan ’ s sign Positive L ö wenberg test Limb size difference > 2 cm