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Caroline S.B. Veen, et al. Thrombophilia: Women-Specific Reference Ranges Can Prevent Misdiagnosis in Women. J Appl Lab Med 2017;2:737-45.
Dr. Caroline Veen. Dr. Veen is currently a graduate student in the Department of Hematology at the Erasmus University Medical Center, Rotterdam.
Hello, and welcome to this edition of “JALM Talk” from The Journal of Applied Laboratory Medicine, a publication of the American Association for Clinical Chemistry. I’m your host, Randye Kaye.
Thrombophilia is a state where inherited or acquired abnormalities of the hemostatic system are present that predispose to thrombosis. During normal pregnancy, major changes and hemostasis occur such as increasing concentrations of most clotting factors, decreasing levels in natural anti-coagulants and impaired fibrinolytic activity. Collectively, these can induce a thrombophilic state, especially in the last trimester. These normal changes in hemostasis resulting from hormonal influence protect women from fatal hemorrhage during delivery.
Complications during pregnancy can contribute to several abnormal physiological thrombotic states including preeclampsia (PE). Preeclampsia is characterized by a maternal hypercoagulable state with intravascular coagulation, microthrombosis in several organs and impairment of the uteroplacental circulation.
The development of preeclampsia during pregnancy can have detrimental effects to both the mother and fetus. The diagnosis of preeclampsia and postpartum thrombophilia remains challenging for certain populations and the use of universal reference ranges may be misleading in these women. Several studies have already highlighted the influence of age, sex, and oral contraceptive hormone use for a coagulation reference intervals. The development and adoption of gender-specific reference intervals for pregnant women is essential for accurate identification of thrombophilic states.
“Thrombophilia: Women-Specific Reference Ranges Can Prevent Misdiagnosis in Women” was published in the March 2018 issue of The Journal of Applied Laboratory Medicine. This work presents the establishment and impact of female-specific reference intervals for a variety of coagulation markers during pregnancy.
The first author is Dr. Caroline Veen. Dr. Veen is currently a
graduate student in the Department of Hematology at the
Erasmus University Medical Center, Rotterdam. She
obtained her medical degree from the VU University in
Amsterdam in 2013 and worked for two years in the
Department of Internal Medicine and the Emergency
Department. She’s our guest for today’s podcast.
Welcome, Dr. Veen.
Let’s start with this question, why are women’s health issues
so important in thrombosis and hemostasis?
Yes, well, thank you for the introduction and for your
Women’s health issues are so important in thrombosis and
hemostasis, specifically, because women experience unique
situations, such as the menstrual cycle, pregnancy and
delivery, in which disturbances of hemostasis may lead to
bleeding problems or thrombosis. For example, it’s known
that over 80% of young women with Von Willebrand
disease, which is an inherited disorder of primary
hemostasis, experience menorrhagia and postpartum
hemorrhage, which is defined as blood loss of more than
500 milliliters within 24 hours after delivery. It’s also still
one of the major causes of maternal deaths in the world and
the prevalence is steadily increasing in many higher
resource countries as well.
Furthermore, pre-existing coagulation disorders are known
risk factors for postpartum hemorrhage. But it’s shown that
even mild hemostatic abnormalities can increase the risk for
severe postpartum hemorrhage. And with regard to
thrombosis, pregnancy is associated with an increase in
concentrations of most regulation factors but also decrease
in concentration as some of the natural anticoagulants which
together induce a thrombophilic state, especially in the last
trimester of pregnancy and the use of hormonal
contraceptives also increase levels of coagulation factors.
So, this leads to a pro-coagulant risk profile and several
studies have shown that currently used combined oral
hormonal contraceptives increase the risk of
thromboembolism two to sixfolds. So yeah, in order to keep
on improving patient care, women-specific health issues
deserve emphasis in the field of thrombosis and hemostasis,
from my opinion.
Okay, thank you. So, keeping that in mind, do you think we
should consider female-specific reference ranges for all
Yes, that’s a very important question, but I think it depends
on the clinical relevance of the test for the target patient
population. There are, of course, several factors that can
cause differences in reference ranges between groups, and
sex being an important factor, as the major difference of
course, between men and young women is the presence of
female sex hormones, which can have an influence on
different test results.
And as we have shown in this study, using women-specific
reference ranges can prevent misclassification or
overdiagnosis of different diseases. But there are, I think,
several arguments also not to have reference ranges for
each different variable that can effect on these reference
ranges. First of all, as I mentioned, it’s important to take
the clinical relevance into account. Some differences are
small, can be considered not being clinical relevant and the
International Federation of Clinical Chemistry and
Laboratory Medicine recommends estimating reference
ranges on at least 120 subjects. And enrolling this many
subjects is difficult, it’s costly, very time-consuming and
lastly, taking into account, all the different variables that
can have an influence on reference ranges. Think of age,
but also dietary habits, or the environment, use of
medication, muscle mass, it’s simply not possible to
calculate reference ranges for each of these different
So, inclusion of each variable specific reference range,
including sex, to my opinion, should primarily be based, I
think, on the clinical relevance for the charted population.
Okay, thank you. So, it’s certainly not across the board
always important or easy to get, but certainly sometimes,
it’s important. If we consider female-specific reference
ranges in thrombosis and hemostasis, should we also
consider adjusted reference intervals for women who are
using oral contraceptives?
Me and my supervisor had a lot of discussion about this
specific issue. So, in the best scenario, of course, especially
with regard to hemostasis, we would like to have different
values for women with and without the use of hormonal oral
contraceptives because of the earlier-mentioned influence of
contraceptives on hemostasis.
However, as we see in our center, the diagnostic process of
congenital thrombophilia in this case, but also the more rare
coagulation disorders, is very challenging and is not
necessarily carried out in routine laboratory in the
Netherlands. So, therefore, our physicians are often
consulted by physicians from regional hospitals and information about the use of oral contraceptives may not
always be known to the consult physician.
And because the contraceptive is still used in such a large
group of young women—I believe a few years ago, it was
more than one-third of the young women in the
Netherlands. In this study, we decided to include women
using oral contraception in the women-specific reference
Okay, thank you and one final question, at which time point
after pregnancy, would you recommend testing women for
Also, a very important issue to be addressed. When I look
into our clinic, we usually advise to test women at least
three months after pregnancy, because then we believe all
the effects of pregnancy and hemostasis have diminished.
And initially in this study, we also wanted to investigate
differences in hemostatic factors three and six months after
pregnancy but unfortunately, the study design was not
appropriate to answer this question.
There are some studies and there’s one study published in
2016, where the authors investigated reference ranges in
healthy population and they stated in their results that
values 8 to 12 weeks after delivery were not different from
healthy, non-pill using women and this was tested in a
group of over 160 women.
A lot of studies however, when they investigate hemostatic
variables after pregnancy, only measured coagulation
factors the first days after delivery, usually the first one, two
or three days, and not much is known about the period
these days and eight weeks after pregnancy. So, I would
recommend based on several studies to test for
thrombophilia, for hemostasis in general, at least eight
weeks after delivery.
That was Dr. Caroline Veen, from Erasmus University
Medical Center in Rotterdam, talking about “Thrombophilia:
Women-Specific Reference Ranges Can Prevent Misdiagnosis
in Women” from the March 2018 issue of JALM for this
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