Case Report

DEEP VENOUS THROMBOSIS (DVT)

ANDALAS UNIVERSITY

By:

dr. Aswin Boy Pratama, SpOG

Trainee of Fetomaternal Subspeciality Education
Program

Mentor:
Prof. Dr. dr. Hj. Yusrawati, SpOG, Subs-KFM
(K)
Dr. Dr. dr. Joserizal Serudji SpOG, Subs-KFM
(K)

FETOMATERNAL SUBSPECIALITY EDUCATION PROGRAM

OBSTETRICS AND GYNECOLOGY
MEDICAL FACULTY OF ANDALAS UNIVERSITY
2024
 PROGRAM STUDI SUBSPESISALIS OBSTETRI DAN
GINEKOLOGI PEMINATAN KEDOKTERAN FETOMATERNAL
FAKULTAS KEDOKTERAN UNIVERSITAS ANDALAS
RSUP Dr. M. DJAMIL PADANG

LEMBAR PENGESAHAN

Nama : dr. Aswin Boy Pratama, SpOG

Semester : I (Satu)

Telah menyelesaikan kasus Kehamilan

dengan Penyulit DVT

Padang, Februari 2024

Pembimbing Peserta Pendidikan Subspesialis Obgyn

Peminatan Kedokteran Fetomaternal

Dr.Dr.dr.Joserizal Serudji SpOG(K) dr. Aswin Boy Pratama,SpOG

MENGETAHUI

KPS SUBSPESIALIS OBGYN

PEMINATAN KEDOKTERAN
FETOMATERNAL FK UNAND

Prof.Dr.dr.Hj.Yusrawati,SpOG(K)
 CHAPTER 1
INRODUCTION

Case: Mrs. Suryani 39 years old 972092, G4P2A1H2 11-12 weeks gestational age
with deep vein thrombosis (DVT) control to fetomaternal. She was diagnosed
DVT by division of vascular in Tertiary Hospital.

Pregnancy and the puerperium are well-established risk factors for venous
thromboembolism (VTE), a disease that includes pulmonary embolism (PE) and
deep venous thrombosis (DVT). Delayed diagnosis, delayed or inadequate
treatment and inadequate thromboprophylaxis account for many of these deaths.
Once diagnosed, DVT must be treated not only to prevent PE, but also to prevent
postthrombotic syndrome (PTS).
 CHAPTER II
LITERATURE REVIEW

2.1 Introduction
Pregnancy and the puerperium are well-established risk factors for venous
thromboembolism (VTE), a disease that includes pulmonary embolism (PE) and
deep venous thrombosis (DVT). Approximately 30% of apparently isolated
episodes of PE are associated with silent DVT and in patients presenting with
symptoms of DVT, the incidence of silent PE ranges from 40–50% (1). VTE is
both more common and more complex to diagnose in those patients who are
pregnant than in those who are not. PE is the leading cause of maternal death in
the developed world (1-5). Delayed diagnosis, delayed or inadequate treatment
and inadequate thromboprophylaxis account for many of these deaths. In this
review, we will focus on DVT during pregnancy, summarizing its risk factors,
pathogenesis, complications, diagnostic criteria and tools, prophylaxis, medical
and endovascular management.

2.2 Epidemiology
Women are up to 5 times more likely to develop DVT during pregnancy than
when not pregnant (1-6). The hypercoagulable state of pregnancy likely evolved
to protect women from excessive bleeding during miscarriage and childbirth. In
fact, in developing nations, hemorrhage is the leading cause of maternal death.
However, in the United States and other developed nations, the leading cause of
maternal death is embolic disease (1-7). The frequency of thrombosis is similar in
all three trimesters, and is also increased in the first 6 weeks of the post-partum
(2,4,6). In addition to the mortality and immediate morbidity, there is also long
term morbidity associated with the postthrombotic syndrome (PTS). The majority
of women, who suffer from DVT during pregnancy, develop sequelae that range
from edema and skin changes to recurrent thrombosis and ulceration (6).
Certain conditions have been associated with the highest risk of pregnancy
related DVT. These include inherited or acquired thrombophilias, a previous
history of thrombosis, antiphospholipid syndrome, lupus, heart disease and sickle
cell disease (4). When these are present, the need for prophylactic anticoagulation
should be addressed (4). Other independent risk factors are age 35 and older, null
parity, multiple gestations, obesity and immobility, these increase the risk 1.5–2
fold (4,7). Two studies, James et al. and Jacobsen et al., also found an association
between gestational diabetes and thrombosis (4,7). Although data is limited,
assisted reproduction is also considered a risk factor (7). In the puerperium, post-
partum infection increases the risk of thrombosis by 4-fold and cesarean delivery
increases the risk 2-fold (4). Jacobsen et al. and Lindqvist et al., found a higher
prevalence of venous thrombosis in the postnatal period among patients with
preeclampsia (7-9).

2.3 Pathogenesis of DVT during pregnancy

Pregnancy is a prothrombotic state; it has all components of Virchow’s triad:
venous stasis, endothelial damage and hypercoagulability. Venous stasis results
from a hormonally induced decrease in venous tone and obstruction of venous
flow by the enlarging uterus. A reduction of venous flow velocity of
approximately 50% occurs in the legs by weeks 25–29 of gestation. This lasts
until approximately 6 weeks postpartum, at which time normal venous velocities
return (10,11). Among pregnant and postpartum women, the left lower extremity
is the most common site of DVT (82%). Anatomic reasons (compression of the
left common iliac vein by the right common iliac artery which is accentuated by
the enlarging uterus) have been postulated (6).
Endothelial damage in pelvic veins can occur at the time of delivery or
from venous hypertension (2). Pelvic vein thrombosis, which is uncommon
outside of pregnancy, accounts for 6–11% of DVT during pregnancy and the
puerperium (6).
During normal pregnancy, a hypercoagulable state is initiated. This is the most
important risk factor contributing to thrombosis during pregnancy. Fibrin
generation is increased, fibrinolytic activity is decreased, levels of coagulation
factors II, VII, VIII and X are all increased (2,12). There is a progressive fall in
protein S levels and acquired resistance to activated protein C (2,12). All of these
changes reflect the physiological preparation for the hemostatic challenge of
delivery. This hemostatic activation is demonstrated by increased markers of
hemostatic activation, such as prothrombin fragment F1+2 and D-dimer (1,12).

2.4 Risk assessment and prophylaxis for DVT/VTE

Despite the increased risk for thrombosis during pregnancy and the postpartum
period, most women do not require anticoagulation. In most cases the risks of
anticoagulation outweigh its benefits. The risk of maternal bleeding complications
with heparin and low molecular weight heparin (LMWH) is reported to be as high
as 2% (13). Thromboprophylaxis during pregnancy is problematic because it
involves long term parenteral LMWH or unfractionated heparin (UFH). Both are
expensive, inconvenient and painful to administer and are associated with risks of
bleeding, osteoporosis and heparin induced thrombocytopenia (HIT); although
these complications, particularly HIT are very uncommon with LMWH (14,15).
Given its benefits compared to UFH, LMWH are the preferred agent for
prophylaxis and treatment of DVT during pregnancy (14,15). A disadvantage of
LMWH over UFH is its longer half-life, which may be a problem at the time of
delivery.
UFH is preferred in patients with renal insufficiency, as LMWH is
primarily excreted by the kidneys and may accumulate in those with severe renal
dysfunction (15). Warfarin crosses the placenta and is teratogenic, it is a US FDA
category D drug. Warfarin is associated with a 14–56% reported risk of
miscarriage during the first trimester and carries up to 30% risk for congenital
anomalies (16-19) when taken during the critical period of organogenesis (4 th–
8th week after conception). Placental transfer of warfarin later in pregnancy can
result in fetal bleeding (20) or still birth (16-19). Long term sequelae include a
14% reported risk of adverse neurologic outcome and a 4% reported risk of low
intelligence quotient (IQ) (21). Data for the use of fondaparinux, a selective factor
Xa inhibitor, during pregnancy is limited. Although studies using models did not
show passage through the placental barrier (20), Dempfle et al. found it crossed
through the placenta in five women who took it for 1–101 days because of heparin
allergy (22). Anti-factor Xa levels in the umbilical cord plasma of the newborns
was found to be one tenth the concentration of maternal plasma. The clinical
significance of this is unknown, but no adverse effects were noted on the
newborns (22). At present time there is insufficient data to support the routine use
of fondaparinux for prophylaxis of VTE during pregnancy. It is reserved for those
cases of severe cutaneous allergy to heparin or HIT. Small case series and case
reports have shown it to be safe (22-24) but it is important to recognize that most
of these involve exposure during second and third trimesters. Other factor Xa
inhibitors (e.g., dabigatran, rivaroxaban, apixaban, edoxaban) are likely to cross
the placenta and their human reproductive risks are unknown (15).
Determining which patients should receive thromboprophylaxis has
always been a challenge. Its rational administration depends on identifying those
women who have an increased risk of thrombosis and accurately quantifying this
risk. The threshold for recommending post-partum prophylaxis is lower than for
antepartum prophylaxis due to the shorter length of required treatment (up to 6
weeks), the higher average risk of DVT in the postpartum and the safety of
warfarin during this time, even if the mother is breastfeeding (not excreted in
breast milk) (14). The relatively equal distribution of DVT throughout all
trimesters suggests that when antepartum prophylaxis is warranted, it should be
initiated early in the first trimester
During pregnancy, a history of hereditary or acquired thrombophilia or a
history of previous DVT has been determined to be the most important risk
factors. The risk becomes even higher if the maternal age is >35 years or if there
are other additional independent risk factors such as obesity, immobility, null
parity, multiple gestations (4-7) or smoking (25). In the post-partum period,
hypertension (probably due to preeclampsia), immobility and recent surgery (C-
section) appear to be the most important independent risk factors. Available data
suggest that women with a history of previous venous thrombosis have an
increased risk of recurrence during pregnancy. Although it is estimated that the
risk is within 2–10%, the absolute rates of recurrence are unknown. There have
been no large clinical trials assessing the role of prophylaxis in pregnant women
with prior DVT. There is an ongoing multinational randomized controlled
prospective trial, the Highlow study, which is recruiting pregnant women with a
previous history of venous thrombosis and an indication for thromboprophylaxis.
Its aim is to determine the true risk of recurrent VTE, the optimal dose of LMWH
for prophylaxis and its safety. The Netherlands, France, Ireland, Belgium and
Norway are participating; they will be enrolling patients through 2019, with an
expected sample size of approximately 1,000 women. The results are expected by
2020 (26).
Congenital thrombophilias are present in at least 15% of the general
population and approximately 50% of gestational venous thromboses are
associated with heritable thrombophilias (27). Multiple studies have looked at the
relationship between hereditary thrombophilias and VTE. However, limitations in
their methods have made it difficult to make accurate assessments of their risk.
The highest risk has been found with homozygosity for factor V Leiden and
homozygosity of the prothrombin G20210A variant (14). The more common
inherited thrombophilias such as heterozygous factor V Leiden and heterozygous
prothrombin variant were associated with lower risk (14). Deficiencies of
endogenous anticoagulants such as antithrombin, protein C and protein S were
associated with moderate risk (14). Given the background incidence of VTE
during pregnancy of approximately 1/1,000 deliveries, it is clear that the absolute
risk of VTE in women without a prior event remains modest for those women
with the most common inherited thrombophilias. Acquired thrombophilias have
been less well studied, but persistent APLAs (lupus anticoagulants or
anticardiolipin antibodies) are likely associated with an increased risk of
pregnancy related VTE (14). The American College of Obstetricians and
Gynecologists (ACOG) recommends testing for antiphospholipid antibodies and
inherited thrombophilias if there is a prior history of VTE (15).
The American College of Chest Physicians (ACCP) and ACOG
recommend prophylaxis with LMWH for all pregnant patients with a previous
history of venous thrombosis and documented thrombophilia, as well as for those
with a history of multiple (>2) episodes of DVT (14,15). There is no consensus on
what the ideal dose should be, the recommendation is for prophylactic,
intermediate or adjusted dose (Table 1) (14,15). For patients with history of a
single idiopathic DVT, but no thrombophilia or those with a transient risk factor
that has resolved, the recommendation from both agencies is for close clinical
surveillance during pregnancy and prophylaxis postpartum (14,15). For pregnant
patients with a heritable or acquired thrombophilia but no prior history of venous
thrombosis, the recommendation of the ACCP is not to routinely use prophylaxis
antepartum, but to perform an individual risk assessment; however, postpartum
anticoagulation is recommended (14). For those with antithrombin deficiency, the
ACCP recommends antepartum and postpartum prophylaxis (14). The ACOG
recommends prophylaxis for all women with documented thrombophilia during
the antepartum and postpartum (15). LMWH should be discontinued the moment
that the women are in established labor, or think they may be in labor and 24
hours prior to planned C-section (15). Switching from LMWH to UFH may be
considered during the last month of pregnancy, as it has a shorter half-life (15).
Limited data is available on assisted reproduction as a risk factor. The
cases reported are related to severe hyperstimulation syndrome, which happens in
0.5–6.5% of all hyperstimulations (7). This syndrome is associated with
hemoconcentration and has very high levels of estradiol. Ascites and pleural
effusions are common. These clinical presentations, combined with immobility
and pregnancy induced hypercoagulability make these women particularly
predisposed to venous thrombosis (7). These patients should be under close
clinical surveillance for VTE. More recently, several groups have suggested the
use of scoring systems to aid with risk assessment. One of these groups,
Dargaud et al., has postulated the use of the Lyon VTE risk score as a means of
providing a rational decision process to implement safe and effective antepartum
thromboprophylaxis in pregnant women at high risk of DVT (28). The Lyon
score, assesses the risk of VTE during pregnancy according to three main criteria:
history of previous VTE, known thrombophilia markers and contemporary risk
factors dependent on the current pregnancy.

2.5 Diagnosis of DVT in the pregnant woman

The most common presenting symptoms of DVT are swelling in 88% of pregnant
women and 79% of postpartum women and extremity discomfort in 79% of
pregnant women and 95% of postpartum women (6). Additional symptoms
include difficulty walking, in 21% of pregnant and 32% of postpartum women.
Erythema was reported in 26% of both groups (6). The incidence of isolated DVT
in the iliac veins is higher during pregnancy (6). Isolated iliac vein thrombosis
may present with abdominal pain, back pain and/or swelling of the entire leg
(1,6). These symptoms may be masked by the swelling and discomfort that
accompany normal pregnancies, making the diagnosis of DVT during pregnancy
more challenging.
Stasis and swelling of the legs can occur due to mechanical compression of the
lymphatic vessels and veins which happens with the enlarging uterus. Therefore,
edema is a less reliable sign of DVT in pregnant women. Pelvic and back pain
may be misinterpreted as normal/expected discomfort or due to musculoskeletal
issues, when these symptoms may be emanating from a proximal (ilio-femoral)
DVT. These non-specific symptoms are often ignored until the thrombus extends
distally into the femoral veins causing pain and swelling of the whole affected leg.
The D-dimer essay is positive even during uncomplicated pregnancies. This
indicates increased thrombin activity and increased fibrinolysis following fibrin
formation throughout pregnancy, the result of the pregnancy related
hypercoagulable state (12). Thus, this test is non-specific and not reliable for the
diagnosis of DVT during pregnancy.
All pregnant women with signs and symptoms suggestive of DVT should
have objective testing performed expeditiously, as sudden death is not uncommon
among pregnant patients with features compatible with VTE (1). Unless
contraindicated, anticoagulation treatment is recommended when the clinical
suspicion is high, until the diagnosis of DVT is ruled out (1). To confirm the
diagnosis in this subset of patients, the use of non-invasive and non-ionizing
imaging is preferable. Both, for the health of the fetus as well as the mother as
ovaries are radiation sensitive. Currently, there are two such non-invasive
methods, ultrasound and magnetic resonance imaging (MRI). Contrast enhanced
computed tomography (CT) may be used to diagnose pelvic DVT when MRI is
not available, but is not ideal, and not routinely recommended, as it is associated
with fetal and maternal radiation exposure.
 Routine ultrasonography for the diagnosis of DVT includes direct
examination of the thrombus with gray scale imaging, compression technique and
color flow Doppler. DVT is diagnosed when the veins fail to compress
completely. Sometimes grey scale imaging can demonstrate the thrombus, but this
may be limited by a large body habitus or by artefactual intraluminal echoes, thus
this is not the primary focus for diagnosis. In obese or very edematous patients,
grey scale imaging is limited and the use of color Doppler is helpful to adequately
localize the vessels. Compression of the calf or plantar flexion can accentuate the
veins, and further assist with adequate imaging.
Compression ultrasonography has a sensitivity of 97% and a specificity of
94% for the diagnosis of symptomatic femoro-popliteal DVT in the general
population (29). Ultrasonography is without risk, inexpensive and readily
available. It is the test of choice for pregnant patients with suspected DVT.
However, it is less accurate for pelvic vein thrombosis, primarily because of their
deep location. Furthermore, the size of the pregnant uterus in the latter half of
pregnancy makes imaging of these veins even more difficult. In addition, the
compression technique is obviously difficult to perform in the pelvis and much
more so in the pregnant pelvis.
A study by Torkzad et al. found, in women between 23 and 37 weeks of
gestation, that ultrasound revealed 42% of pelvic and abdominal DVT whereas
MRI 98.5% (30). Ultrasound should continue to be the primary method of
diagnosis of DVT, but if the ultrasound is negative and clinical suspicion is still
present, one should not hesitate to order an MRI. MRI is also useful in cases
where determining the true extent of a DVT into the pelvis/abdomen will
influence management. Imaging protocols without gadolinium are preferred. Pulse
sequences such as 2D time of flight with arterial flow suppression and T1
weighted gradient echo with fat saturation are used (30). On the T1 weighted
images, high signal intensity within a vein represents methemoglobin in the
thrombus, indicating an acute thrombus. Enlargement of the vein and perivascular
inflammation are also signs of acuity (30).

2.6 Clinical outcomes and management

Once diagnosed, DVT must be treated not only to prevent PE, but also to prevent
PTS. Moderate to severe PTS is a debilitating chronic outcome of proximal DVT.
It has been suggested that PTS is due to incomplete recanalization and/or
permanent damage to the venous valves resulting in valvular reflux (31). Its
pathophysiology is not well understood, but it manifests clinically as leg
heaviness, fatigue, aching and edema (32). Severe PTS may result in venous
ulcers (32). PTS may occur in as many as 60% of patients after acute DVT
involving the iliac and/or femoral vein segments (33). In a study by Chang et al.,
looking at long term outcomes in pregnancy related DVT, they found that 42% of
women with lower extremity DVT developed PTS, which was severe in 7% (34).
Medical management is the first line of therapy for DVT. As with prophylaxis,
LMWH is the drug of choice for therapy, at full therapeutic or adjusted dose
(14,15). Here, we will focus on inferior vena cava (IVC) filter placement and
pharmacomechanical catheter directed thrombolysis (PCDT).
 CHAPTER III
DISCUSSION

Women are at increased risk of VTE during pregnancy and the postpartum period.
Treatment and prevention of VTE in this patient population is complicated by the
need to consider fetal, as well as maternal wellbeing when making management
decisions. Although our knowledge of risk factors for pregnancy related VTE, the
safe and effective use of anticoagulants in this patient population, as well as the
use of IVC filters and catheter directed therapies continues to grow, there are still
important gaps. The lack of high quality research and conclusive trial data
demonstrating the safety and efficacy of treatment options for VTE during
pregnancy highlights the need for prospective trials with larger numbers of
patients.
All women must be provided with the opportunity to participate in shared decision
making regarding their management. To make the best decisions, absolute risks
and benefits of interventions, guideline recommendations and the patients’ values
and preferences must all be taken into account.
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