Dr. Pallavi Raj (MS, DNB) is currently working as Clinical Assistant under Dr. Sadhana K Desai in The Fertility and IVF Centre, Mumbai. She graduated from G.S.V.M. Medical College, Kanpur, and she did her post-graduation from S. N. Medical College, Agra. She has also received training in Fetal and Gynecological Imaging from Nowrosjee Wadia Maternity Hospital, Mumbai. She has special interest in reproductive endocrinology, high risk obstetrics and endoscopy. She had won Dr. D. K. Tank prize in oral paper presentation in MOGS conference (Mumbai) 2019 for the this interesting case.
Pregnancy itself is a hypercoagulable state due to alteration
in the level of coagulation proteins. Thrombophilia in
pregnancy further complicates it by leading to arterial and/
or venous thrombosis resulting in increased feto-maternal
risk. Thrombosis in maternal veins may lead to deep venous
thromboembolism (DVT) and in placental circulation may
lead to recurrent pregnancy loss (RPL), pre-eclampsia,
abruption placentae, fetal growth restriction (FGR), intrauterine
fetal death (IUFD), still birth. Protein C (PC) and protein
S (PS) deficiencies are included under low-risk inherited
thrombophilias. Both PC and PS deficiencies are associated
with a variably increased risk of thrombosis. Combined
deficiency of protein C and protein S is rare, and only few
confirmed cases have been reported.
Adenomyosis manifests as an enlarged, globular uterus
that can result in heavy menstrual bleeding and dysmenorrhea
but is often asymptomatic. There is an association
between adenomyosis and adverse pregnancy outcomes,
including fetal loss, preterm delivery and preterm premature
rupture of membranes (PPROM), IUGR [1].
A 29-year-old female, married for 3 years, presented with
complaints of 3 recurrent first trimester pregnancy losses.
On detailed history, it was revealed that all 3 conceptions
were spontaneous, and miscarriages (spontaneous) were
between 6 and 8 weeks which were medically managed. She
was thoroughly evaluated for her bad obstetric history. She
had no history of any thromboembolic event. In her thrombophilia
screen, she was diagnosed with Protein C (PC) and
Protein S (PS) deficiency, both functional and immunogenic
[Protein C (functional): 57% (70–130%), ELISA: 40%
(80–140%); Protein S (functional): 50% (73–104%); ELISA:
30% (80–140%); LA (by dRVVT): 27 s (36–50), SLE ruled
out]. She was referred to a hematologist for consultation in
view of PC and PS deficiency Tablet aspirin 75 mg OD was
started thereafter.
USG plate of adenomyotic uterus.
On per abdominal examination, her uterus was found to be
grossly enlarged, approximately up to 20 weeks size. On ultrasonography
(USG) severely adenomyotic uterus was diagnosed with uterus size measuring 14.4 × 9.4 cm with thickened echogenic
walls. MRI revealed uterus size of 17 × 15 × 13 cm, with
multiple small variable areas of heterogeneous echotexture
seen scattered in myometrium (adenomyotic). Her menstrual
cycles were regular with no menstrual abnormality. Decision
for in vitro fertilization (IVF) was taken in view of grossly
enlarged adenomyotic uterus which required medical treatment
to reduce the size of uterus, after counseling the patient and her
family. Her oocyte retrieval was done using antagonist protocol,
and embryos were cryopreserved after fertilization. Before
doing the embryo transfer, her grossly enlarged sized uterus
size was required to be reduced, in order to retain pregnancy.
So, for this purpose total 4 doses of gonadotropin-releasing
hormone (GnRH) analogue, triptorelin 3.75 mg were given
intramuscularly, with 4-week interval between subsequent
doses. After that, USG was repeated which showed significant
reduction in the size of uterus, measuring 9.7 × 9.1 × 6.6 cm.
Thereafter 3 embryos were transferred after thawing. Patient
was diagnosed with twin pregnancy. Injection low molecular
weight heparin (LMWH), i.e., enoxaparin 40 mg subcutaneously
OD, was started. Routine antenatal care was provided.
At 8 weeks of gestational age, she had bleeding per
vaginum for which she was admitted in the hospital and
was managed conservatively for threatened abortion. Tablet
aspirin was stopped, and LMWH was continued along
with progesterone support. Her B.P. was within normal
range throughout pregnancy, although hypertension is often
noticed in such cases of thrombophilia. Decision for Elective
LSCS at 37 weeks was taken in view of transverse lie
of one of the twin fetus. LMWH was stopped a day before
LSCS. And 2 units of PCV were cross-matched. A healthy
male baby (vertex) weighing 3100 g and a healthy female
baby (transverse) weighing 2090 g were born, both alive and
well now. Uterus was found to be severely adenomyotic and
enlarged. Intra-operatively, patient landed up in post-partum
hemorrhage and mild DIC. Uterotonics like Inj. Oxytocin
20 units in 500 ml Ringer lactate was given intravenously,
Inj. Methergine 0.2 mg was given intravenously, and in
addition 800 μg of Tab. misoprostol was kept per rectally. 3
units packed cell volume (PCV) was given, and patient was
shifted to ICU. Post-operatively 3 more units of PCV and 4
units of fresh frozen plasma (FFP) were required to be given.
Thromboembolic deterrent (TED) stockings were advised.
Patient was shifted to ward on post-op day 3, and LMWH
was restarted and was advised to continue for 6 weeks postpartum.
Patient was discharged on post-op day 6.
Inherited deficiencies of the natural coagulants are uncommon.
Protein C deficiency occurs in approximately 1 of
every 200–500 people, whereas protein S deficiency can be expected in approximately 1 of every 500 individuals
[2]. Only a few cases of combined PS and PC deficiency
have been reported in literature, so its prevalence rate is
still not established. It is a unique case of pregnancy and
related complications in a patient with combined PS and
PC deficiency with adenomyosis, as no similar case is
yet reported in scientific papers. The deficiency of clotting
inhibitors, like PS, PC and/or antithrombin, has been
clearly associated to RPL in many past studies. The association
between thrombophilia and recurrent pregnancy
loss (RPL) has become an undisputed fact [3]. PC and PS
deficiency tests should be done in pre-pregnancy state,
as results are less reliable in pregnant state because during
pregnancy resistance to the anticoagulant protein C is
increased, and the protein S level, a cofactor to protein C,
decreases. To manage these patients, the antithrombotic
therapy plays a vital role. Patients who have no personal
history of VTE, as was our patient, are advised prophylactic
dose of LMWH with or without aspirin, whereas
the patients with history of VTE should be advised intermediate
or therapeutic dose of LMWH. These patients
should be closely monitored for other risks associated
with thrombophilia throughout pregnancy. Mostly patients
with thrombophilia may never develop VTE, but there is
always certain risk of developing VTE in pregnant patients
having thrombophilia. Chaudhari et al. [4] also reported
such a case of combined PS and PC deficiency who had
4 RPL and developed superior sagittal sinus thrombosis
post-operatively.
Adenomyosis interferes with natural conception and
normal implantation. GnRH analogues are used for medical
management and exert a direct antiproliferative action
on myometrium. GnRH agonists can markedly reduce the
inflammatory reaction and angiogenesis; it also induces
apoptosis in adenomyotic tissues. It overall results in shrinking
enlarged adenomyotic uterus [5]. In 2017, a metaanalysis
suggested that adenomyosis reduces the chance for pregnancy
and increases the risk for miscarriage, and GnRH may
be beneficial in such cases [6]. The progesterone receptors
present on endometrial tissue and the elevated progesterone
levels in pregnancy result in stromal decidualization of
adenomyosis foci. This heavily decidualized adenomyosis
can then lead to uterine wall weakness, further resulting in
uterine rupture or uncontrolled bleeding during pregnancy.
In a case reported by Tatsis V, et al., at the time of LSCS,
extensive transmural adenomyosis with decidualization was
noted, ultimately requiring a Cesarean hysterectomy due to
intra-operative hemorrhage. Similarly our patient had intraoperative
hemorrhage but fortunately could be managed
conservatively. Thus, it is important to counsel patients
regarding the potential implications of suspected adenomyosis
where clinically relevant and to consider maternal–fetal
outcomes.
Conflict of interest The authors declare that they have no conflict of interest.
