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Consultative hematology II:
womens health issues
Margaret V. Ragni, Peter A. Kouides, and Sarah H. OBrien
The role of a multidisciplinary team Thromboembolism and thrombophilia Conclusion, 77
in managing women with blood inpregnancy, 64 Bibliography, 77
disorders, 53 Hematologic health issues in the
Hematologic health issues in premenopausal woman, 71
pregnancy, 54

The role of a multidisciplinary hospital, the role of a hematologist specifically trained in

team inmanaging women with womens health issues is essential to ensure optimal out-
blood disorders comes. Furthermore, the plan of care should be formulated
with the multidisciplinary team, when available, utilizing
The diagnosis and management of womens health issues in evidence-based guidelines from expert panels of the National
hematology require a multidisciplinary approach involving Heart, Lung, Blood Institute (NHLBI); National Hemophilia
some combination of hematologists, internists, family prac- Foundation (NHF); American College of Obstetrics and
tice physicians, obstetrician gynecologists, pediatricians, sur- Gynecology (ACOG); American College of Chest Physicians
geons, anesthesiologists, and other health care providers. (ACCP); and World Health Organization (WHO) and should
Because women and girls with blood disorders may be at be communicated in a timely manner with all consulting care
greater risk for bleeding, thrombosis, and reproductive preg- providers as well as the patient. This chapter summarizes the
nancy complications, their care requires a team of experts most recent evidence and guidelines available to minimize
with the availability of specialized laboratory, pharmacy, and risk in the woman with blood disorders, in particular in
blood bank support (Table 3-1). Whether the patient is an thepregnant woman and in the premenopausal female.
adolescent, pregnant, or a perioperative or critically ill female The hematologist may play a critical role, directly orindi-
patient, or whether the setting is inpatient, outpatient, or rectly, in the care of such patients, in a number of scenarios,
phone consultation with a nearby emergency room or whether serving on hospital committees, working groups,
and formulary committees, or developing clinical practice
guidelines, establishing policies and procedures for transfu-
Conflict-of-interest disclosure: Dr. Ragni: research support from sion services, monitoring quality of care and service effi-
Alnylam, ATHN, Baxalta, Biogen, CSL Behring, Dimension, Genen- ciency, developing practice guidelines, or consulting for the
tech Roche, Novo Nordisk, Novartis, Opko, Pfizer, Shire, SPARK, and federal government or pharmaceutical industry. Although
Vascular Medicine Institute; consultant for Baxter, Bio-Marin, Biogen,
Medscape, Opko, Tacere Therapeutics; member of the National He- these latter roles are not addressed specifically in this chapter,
mophilia Foundation Medical & Scientific Advisory Committee and the data management, organizational, and communication
Foundation for Women and Girls with Blood Disorders Advisory skills required for providing patient care or providing patient
Board. Dr. Kouides: consultant for Baxter, CSL Behring, Grifols; mem-
ber of the National Blood Clot Alliance Medical & Scientific Advisory
consultation are just as critical as those required when work-
Board. Dr. OBrien: research support from Bayer and the Hemophilia ing on advisory groups. The clinical hematologist also serves
Thrombosis and Hemostasis Research Society of North America patients well when adhering to the principles of effective
(HTRS); serves on an advisory board for GlaxoSmithKline.
communication in work with other physicians and consul-
Off-label drug use: Dr. Ragni: not applicable. Dr. Kouides: low-
molecular-weight heparin, fondaparinux, aspirin, and warfarin in tants, house staff, fellows, students, and the patient and
pregnancy. Dr. OBrien: not applicable. family. A commitment to effective multidisciplinary team

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54 | Consultative hematology II: womens health issues

Table 3-1 Principles of management of womens hematologic health issues

Principle Comment
Women with blood disorders are at increased Establishing diagnosis of a blood disorder as early as possible, preferably preconception,
risk for complications of pregnancy and the is essential in optimal management of women with blood disorders. A prediagnosis
menopausal period, including bleeding and should be based on clinical and laboratory assessment. A personal and family
clotting in the antepartum, peripartum, and history of bleeding or clotting, drug history (including hormonal agents), previous
postpartum periods. pregnancy loss, or pregnancy complications should be determined.
Perform laboratory testing for presence of a For a woman with suspected blood disorder, a bleeding or thrombotic complication of
blood disorder (eg,a hemostatic disorder), as pregnancy, or disorder predating pregnancy, a thorough history, clinical assessment
indicated by personal and family history. should be obtained, and laboratory testing performed as indicated.
Involve a multidisciplinary team in the General management requires a multidisciplinary team, including hematologist,
management of women with blood disorders, internist, obstetrician-gynecologist, family practitioner, pediatrician, anesthesiologist,
and develop and discuss the plan with the and surgeon, and the availability of specialized laboratory, pharmacy, and blood
patient. bank support.
Develop a management plan with the Patient management should be coordinated with the multidisciplinary team. Specific
multidisciplinary team with patient-specific recommendations should be communicated regarding laboratory monitoring,
recommendations. treatment guidelines, including factor, blood products, or antithrombotic agents.
Communicate the management plan for delivery Ensure all management plans are communicated in a timely fashion with all members of
with the multidisciplinary team and discuss the the multidisciplinary team, and also with the patient. Resolve questions and readjust
plan with the patient. to optimize compliance.
Anticipate postoperative, postprocedure therapy, Initiate postprocedure, postdelivery, postoperative planning before the event, and
including duration and where and by whom it include plans for the dose, duration, and location of postprocedure care, involving
will be given. the patient in the decision making.
Offer educational information and guidance. Provide relevant evidence-based literature and guidelines to colleagues and to patients,
as requested.
Provide information to the multidisciplinary team Continue involvement and progress notes as indicated, particularly in vulnerable periods
and patient. such as postpartum. Provide for outpatient monitoring, treatment, and follow-up,
with ongoing communication with the multidisciplinary team and patient.
Adapted from Nichols WL et al. Haemophilia. 2008;14:171-232; MASAC Recommendations regarding girls and women with inherited bleeding
disorders. Medical and Scientific Advisory Committee, National Hemophilia Foundation. 2010;197; and Ragni M. Treatment Strategies-
Hematol. 2012;2:88-92.

collaboration and communication will ensure the highest intrauterine growth retardation and adverse effects on fetal
quality of patient care and optimal patient outcomes. growth when the hemoglobin falls below 8 g/dL.

Iron deficiency anemia

Hematologic health issues
inpregnancy Iron deficiency accounts for 75% of cases of nonphysiologic
anemia in pregnancy, and the incidence of iron deficiency
Anemia in pregnancy
anemia in the United States during the third trimester
During normal pregnancy, the plasma volume expands may exceed 50%. Clinical manifestations of iron deficiency
by40%-60%, whereas the red blood cell mass expands by include fatigue, tachycardia, dyspepsia, poor exercise toler-
20%-50%. Thus, a physiologic anemia develops, leading to a ance, and suboptimal work performance. In addition, iron
normal hematocrit value of 30%-32%. Hemoglobin levels deficiency is associated with postpartum depression, poor
<10g/dL suggest the possibility of a pathologic process, such maternal infant behavioral interaction, impaired lactation,
as nutritional deficiency. The prevalence of anemia in preg- low birth weight, premature delivery, intrauterine growth
nancy increases from 8% in the first trimester to 12% in the retardation, and increased fetal and neonatal mortality. The
second trimester and to 34% in the third trimester. The lat- total iron requirement during pregnancy is 1,190 mg, and,
teris a major indicator of reproductive health. A goal of with a net iron balance during pregnancy of 580 mg, this
Healthy People 2010 was to reduce third trimester anemia equates to a requirement of 2 mg daily. Even with a normal
to20% or less. At present, there is no definitive evidence diet, this is hard to maintain. Besides poor nutrition, other
whether the hemoglobin threshold for transfusion should factors impairing iron absorption include antacids and
be7 or 8 g/dL, although some studies indicate greater risk of micronutrient deficiencies, including vitamin A, vitamin C,

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Hematologic health issues inpregnancy | 55

zinc, and copper deficiency. In the absence of ironsupple- 400 g daily of folate to prevent neural tube defects. Folate
mentation, hemoglobin falls to 10.5 g/dL at 27-30 weeks of deficiency is most precisely diagnosed by measuring plasma
gestation; with iron supplementation, the nadir is less severe, levels of homocysteine and methylmalonic acid.
11.5 g/dL. By the third trimester, serum ferritin declines, Management: For pregnant women, daily folic acid 400 g
erythropoietin levels surge, and maternal hepcidin levels are is recommended.
reduced to facilitate iron transfer and use at delivery.
Current recommendations suggest that pregnant patients
Aplastic anemia
receive 15-30 mg daily of supplemental elemental iron,
although studies examining the efficacy of iron supplemen- Aplastic anemia is rare in pregnancy. It may be either asso
tation during pregnancy have not shown a clear benefit to ciated with or precipitated by pregnancy. Some cases may
pregnancy outcomes. Ferrous gluconate is better tolerated either mimic or occur with idiopathic thrombocytopenia
due to fewer gastrointestinal effects than ferrous sulfate. For (ITP). The mechanism of the bone marrow aplasia that occurs
patients who do not tolerate oral iron, parenteral iron may in pregnancy is believed to be through the erythropoietic
be used. Iron sucrose is categorized as pregnancy class B suppressor effects of hormones during pregnancy. Alterna-
(presumed safe based on animal models) and is preferred tively, preexisting aplasia may be uncovered during preg-
over iron dextran or iron (fumoxytol), which are considered nancy. Aplastic anemia may lead to maternal death in up to
pregnancy class C (safety uncertain). Recent studies have 50% of cases, usually caused by hemorrhage or infection, and
demonstrated that for patients who do not respond well to in utero fetal complications may occur in one-third. Unfortu-
parenteral iron, the addition of recombinant erythropoietin nately, stem cell transplantation, which is the major therapy
may add benefit. In a study of 40 patients with gestational for nonpregnant aplastic anemia, is contraindicated in preg-
iron deficiency anemia who had unsatisfactory responses to nancy. Women with preexisting aplastic anemia have a bet-
oral iron, 20 patients were randomized to receive recombi- ter prognosis than those with pregnancy-induced aplastic
nant erythropoietin (rEPO) and parenteral iron sucrose anemia, although the treatment is similar, including tran
(group 1) and 20 were randomized to receive iron sucrose sfusion to maintain a platelet count >20,000/L, growth
alone (group 2). Patients in group 1 displayed higher reticu- factors (eg, granulocyte colony-stimulating factor [G-CSF]),
locyte counts on day 4, greater increases in hemoglobin from and, in select cases, cyclosporine. Among women who survive
day 11, and a shorter duration of therapy to reach the target pregnancy-associated aplastic anemia, half may experience
hemoglobin of 11 g/dL. No abnormalities in fetal hemoglo- spontaneous remission, and the remainder are managed with
bin levels were observed, consistent with the belief that rEPO antithymocyte globulin, immunosuppression, or stem cell
does not cross the placenta. Thus, although rEPO may func- transplantation.
tion as an adjuvant to iron replacement therapy in pregnant Management: For pregnant women with aplastic anemia,
patients with iron deficiency anemia, it should be reserved transfusions to maintain a hemoglobin 7-8 g/dL, a platelet
for exceptional cases, particularly given the increased risk of count of >10,000/L, and growth factors (eg, G-CSF), as
thrombosis during pregnancy and the fact that improved needed, are recommended. In pregnancy-induced aplastic
fetal outcomes have not been demonstrated. Alternative anemia, the role of termination or early delivery should be
causes of anemia should be sought in patients refractory to considered in management: case reports indicate improve-
standard iron therapy. Finally, although iron supplementa- ment of aplastic anemia following pregnancy.
tion improves hematologic parameters, it may not improve
neonatal outcomes.
Microangiopathic hemolytic anemias
Management: For pregnant women, daily 15-30 mg ele-
mental iron is recommended. For those not able to tolerate Microangiopathic hemolytic anemias are disorders charac-
oral iron, parenteral iron sucrose is preferred. terized by hemolytic anemia in association with thrombocy-
topenia and multiorgan failure. Hemolysis is caused by
microthrombi in small capillaries and is characterized by
Megaloblastic anemia
schistocytes, elevated lactate dehydrogenase (LDH) and
The majority of macrocytic anemias during pregnancy are indirect bilirubin, and reduced haptoglobin. Although they
due to folate deficiency, whereas vitamin B12 deficiency is rare. represent an uncommon cause of anemia in pregnancy (esti-
Multivitamin and folic acid supplementation reduce placental mates are >0.6%-1% of pregnancies are complicated by
abruption and recurrent pregnancy loss. Folate requirements microangiopathies), they may have devastating consequences
increase from 50 g daily in the nonpregnant female to at least for both mother and child. These disorders, which include
150 g daily during pregnancy, and the Centers for Disease thrombotic thrombocytopenic purpura (TTP); hemolytic
Control and Prevention recommend supplementation with uremic syndrome (HUS); preeclampsia; and hemolysis,

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56 | Consultative hematology II: womens health issues

elevated liver function tests, low platelets (HELLP), are chal- control group, while another database of 14,000 deliveries
lenging to diagnose, given the wide overlap in clinical pre- found an increased risk of VTE comparable to that of preg-
sentation, and are difficult to treat, given disparate treatments. nant lupus patients.
These are discussed in the section Thrombocytopenia in Management. The goal during pregnancy is to maintain
pregnancy. Recommendations are provided for each pre-pregnancy hemoglobin and provide more frequent or
disorder. regular transfusions for increasing pain crises or other
complications, eg, chest syndrome. Alloantibody screen-
ing should be performed in early pregnancy, and in heav-
Sickle cell anemia
ily immunized pregnant women, phenotypically-matched
It is well established that pregnancy in women with sickle products should be given if possible. Pregnant SCD
cell anemia is high-risk related to underlying hemolytic patients with a prior history of VTE warrant antepartum
anemia and multiorgan dysfunction. As oxygen demand and postpartum thrombo-prophylaxis (see section
increases to meet the requirements of the growing fetus and Thromboembolism and thrombophilia inpregnancy in
placenta, along with the expanding blood volume, red cell this chapter). For SCD patients without a past history of
requirements increase. Further, pain crises and other com- VTE, while there are no clinical trials, antepartum and
plications may worsen if red cell production cannot keep postpartum LMWH prophylaxis should be considered if
up with oxygen demand. If possible, precipitating factors there are prothrombotic risk factors such as immobiliza-
should be avoided, such dehydration, stress, excessive exer- tion or obesity.
tion, and a cold environment. The problems of oxygenation
and pathophysiology of sickling may result in both mater-
Thrombocytopenia in pregnancy
nal and fetal morbidity. In addition, preeclampsia, eclamp-
sia, placental abruption, and antepartum bleeding may Thrombocytopenia affects 10% of pregnant women and
complicate pregnancy; and pre-term labor, intrauterine results from several disorders that may or may not be specific
growth restriction, and intrauterine fetal death may com- to pregnancy. Pregnant patients may present with isolated
plicate gestation. Nearly half of the women with sickle cell thrombocytopenia or may develop thrombocytopenia as a
disease (SCD) require an acute transfusion due to severe component of a systemic disorder that may be unique to
anemia or obstetric emergency. While there is no specific pregnancy. A summary of causes of thrombocytopenia in
transfusion trigger in pregnancy, the goal is to maintain pregnancy is presented in Table 3-2.
pre-pregnancy hemoglobin. If pain crises escalate, more
frequent or even regular (eg, monthly) transfusions may be
Gestational thrombocytopenia
required. Optimal management of other complications, eg,
acute chest syndrome, may also require more frequent Isolated thrombocytopenia most commonly results from
transfusion. Maternal mortality risk is up to 10% in women gestational or incidental thrombocytopenia of preg-
with SCD pulmonary hypertension. The 2014 NIH Guide- nancy. Gestational thrombocytopenia occurs in 5% of all
lines recommend discontinuing hydroxyurea in pregnancy pregnancies, usually during the second or third trimester,
and during breastfeeding, but few human data exist on and, rarely, in the first trimester, in otherwise-healthy preg-
potential harmful reproductive effects of hydroxyurea in nant women. Thrombocytopenia is usually mild and self-
males and females. It is suggested that iron chelation ther- limited, and by definition, the platelet count does not
apy be discontinued pre-conception. Early in pregnancy decrease below 70,000/L. There is no diagnostic test for
supplemental folic acid at 4 g daily, a higher dose than stan- gestational thrombocytopenia, so it is a diagnosis of exclu-
dardly given in pregnancy should be initiated. Alloantibody sion. This disorder may represent an extreme example of
screening should also be performed early, and, if positive, the typical 10% decrease in platelet count that occurs dur-
phenotypic matching should be considered to avoid delayed ing normal pregnancy. Gestational thrombocytopenia does
hemolytic transfusion reactions or hemolytic disease of the not affect pregnancy outcome and does not result in
newborn. In addition, 10% or more of patients with SCD thrombocytopenia in the offspring of affected women;
will develop a venous thromboembolism (VTE) by adult- thus, no specific treatment is required. It is usually self-
hood, and increased risk is also typical in pregnancy. Con- limited and resolves postpartum, but may recur to the same
tributing risk factors for VTE in SCD may include degree in subsequent pregnancies. As gestational thrombo-
immobilization during hospitalization, vaso-oclusive crisis, cytopenia may not be distinguishable from ITP or more
intravenous access devices, and chronic hemolysis. In one serious disorders in late pregnancy, however, women with
database of 18,000 deliveries, SCD was associated with gestational thrombocytopenia should be monitored
higher rates of cerebral vein thrombosis and DVT than the throughout pregnancy.

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Table 3-2 Differential diagnosis of thrombocytopenia in pregnancy

Severity of MAHA Coagulation Liver Renal CNS
Diagnosis thrombocytopenia defect defect Hypertension disease disease disease Time of onset
ITP Mild-severe Common in first
Gestational Mild Second and
Preeclampsia Mild-moderate Mild Absent-mild Moderate- Proteinuria Seizures in Late second
severe eclampsia to third
HELLP Moderate-severe Moderate- May be Absent-severe Moderate- Absent- Absent- Late second
severe present severe moderate moderate to third
(mild) trimester
HUS Moderate-severe Moderate- Absent Absent-mild Absent Moderate- Absent-mild Postpartum
severe severe
TTP Severe Moderate- Absent Absent-severe Absent Absent- Absent-severe Second to third
severe moderate trimester
AFLP Mild-moderate Mild Severe Absent-severe Severe Absent-mild Absent-severe Third trimester
DIC Moderate-severe May be Absent Absent Absent Absent Third trimester
PNH Moderate-severe Absent Absent Absent Absent Absent All trimesters
Proteinuria measured as total protein excreted in 24 hours is rated as follows: normal is <150 mg/24 h; mild is 150-300 mg/24 h; moderate is
300 mg to 1 g/24 h; severe is 1 g/24 h.
Thrombocytopenia is mild when platelets are >50,000/L, moderate when >20,000/L, and severe when <10,000/L.
AFLP = acute fatty liver of pregnancy; CNS = central nervous system; HELLP = hemolysis, elevated liver function tests, low platelets; HUS =
hemolytic uremic syndrome; ITP = idiopathic thrombocytopenic purpura; MAHA = microangiopathic hemolytic anemia; TTP = thrombotic
thrombocytopenic purpura; DIC = disseminated intravascular coagulation.

Management: No treatment is recommended, as the disor- intravenous immunoglobulin (IVIg) are the first-line treat-
der generally resolves postpartum. ments for maternal ITP. Prednisone is given initially at
lowdose, 10-20 mg/day, with adjustment to the minimum
dose providing a hemostatically effective platelet count.
Immune thrombocytopenic purpura
Although short-term, low-dose prednisone is considered
ITP affects approximately 1 in 10,000 pregnancies. In con- effective and safe in the mother, it may exacerbate hyperten-
trast to gestational thrombocytopenia, ITP is usually detected sion, hyperglycemia, osteoporosis, weight gain, and psycho-
in the first trimester. The diagnosis is a clinical one, as anti- sis; and, in the fetus, may increase cleft palate. Intravenous
body testing lacks specificity. A prior history of thrombocy- anti-D has been used successfully to treat ITP in Rh(D)-pos-
topenia or autoimmune disease preceding pregnancy or itive women, although only a few patients have been reported,
during previous pregnancies is useful in making a diagnosis and thus, the safety of this agent cannot be considered estab-
of ITP. Patients with ITP generally present with more severe lished. Similarly, there is little experience with the use of
thrombocytopenia than those with gestational thrombocyto- rituximab in pregnant individuals, although B-cell lympho-
penia, but the two disorders may be indistinguishable when cytopenia has been reported in the offspring of individuals
ITP is mild. Indications for treatment of ITP in pregnancy in treated with this agent, which is considered pregnancy class
the first two trimesters include: (i) when the patient is symp- C. The thrombopoietic agents romiplostim and eltrombopag
tomatic, (ii) when platelets fall <20,000-30,000/L, or (iii) also are considered pregnancy class C, and a registry has been
toincrease platelet count to a level considered safe for proce- developed for patients taking these agents who become preg-
dures. Although the lowest platelet count safe for spinalor nant. The use of cytotoxic therapy is associated with terato-
epidural anesthesia is controversial, most obstetric anesthe- genicity in many cases, although azathioprine commonly has
tists recommend a platelet count of 75,000/L, and most been used in pregnancy with apparent safety.
hematologists recommend for at least 50,000/L for cesar- Management: For pregnant women, IVIg is recommended
ean delivery. Therapy of ITP in pregnancy is similar to that for severe ITP. In those with severe ITP refractory to steroids
in patients who are not pregnant. Corticosteroids and and IVIg, splenectomy should be considered, optimally in

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58 | Consultative hematology II: womens health issues

the second trimester, when the risk of inducing premature dysfunction occur in preeclampsia has led to studies of anti-
labor is minimized and the gravid uterus does not yet obscure platelet agents, primarily low-dose aspirin, in women with
the surgical field. preeclampsia. In a recent Cochrane review of 43 randomized
Up to 10% of the offspring of patients with ITP also will trials including over 32,000 patients, antiplatelet agents sig-
be thrombocytopenic, and 5% will have platelet counts nificantly reduced preeclampsia in both women at low and
<20,000/L. There are no maternal laboratory studies that high risk for preeclampsia, if started before 20 weeks gesta-
reliably predict whether an infant of a mother with ITP will tion. Although the use of antithrombotic therapy, primarily
be born thrombocytopenic; perhaps the best indicator is a lowmolecular weight heparin (LMWH), has been suggested
prior history of thrombocytopenia at delivery in a sibling. by some for management of high-risk preeclampsia (those
Moreover, no maternal interventions have been shown con- with past preeclampsia, a body mass index [BMI] >35 kg/m2,
vincingly to increase the fetal platelet count. The delivery of preexisting diabetes, twin pregnancy, family history of pre-
the offspring of mothers with ITP by cesarean delivery has eclampsia, chronic hypertension, renal disease, autoimmune
not been shown to reduce the risk of fetal intracranial hem- disease, or an underlying angiotensin-converting enzyme
orrhage, a rare complication affecting <1% of these infants at insertion or deletion polymorphism), its use remains equiv-
delivery; however, some continue to advocate this approach, ocal. In an observational study of women at high risk for pre-
particularly when a sibling previously has been found to be eclampsia, the addition of LMWH to aspirin resulted in no
severely thrombocytopenic at delivery. These considerations greater risk reduction than with aspirin alone, whereas a
and the appreciation that the risk of bleeding with fetal plate- more recent study of high-risk women with thrombophilia,
let count determination by percutaneous umbilical cord found dalteparin resulted in lower risk for severe preeclamp-
blood sampling (PUBS) is greater than that of fetal intracra- sia, low birth rate, or placental abruption than no dalteparin.
nial hemorrhage during vaginal delivery explains the aban- Caution should be taken in interpreting these results, as it is
donment of PUBS in recent years. not known whether findings in women with angiotensin-
Management: All offspring of patients with ITP should be converting enzyme (ACE) mutations apply to all women
monitored closely for the development of ITP within the with preeclampsia. Finally, disseminated intravascular coag-
first 4-7 days after delivery, and all thrombocytopenic neo- ulation (DIC) also may accompany severe preeclampsia and
nates should undergo cranial ultrasound. For severely may be initiated by such processes as retained fetal products,
affected offspring, IVIg is recommended. placental abruption, or amniotic fluid embolism. In these
settings, DIC can be severe, abrupt, and fatal if not managed
appropriately. Recent studies have indicated that LMWH
Preeclampsia and eclampsia
may reduce the rate of recurrent hypertensive disorders of
Thrombocytopenia also may occur in patients with pre- pregnancy before 34 weeks gestation.
eclampsia. Preeclampsia affects 6% of all first pregnancies Management: For pregnant women considered to be at
and usually develops in the third trimester; its diagnostic fea- risk for preeclampsia, and for those with a previous history
tures include hypertension and proteinuria (>300 mg/24h). of preeclampsia, low-dose aspirin (but not thromboprophy-
Preeclampsia occurs most commonly in primagravidas <20 laxis) starting in the second trimester.
and >30 years of age. Eclampsia, defined by the presence of
grand mal seizures accompanying preeclampsia, complicates
Hemolysis, elevated liver function, low platelets
<1% of preeclamptic pregnancies. Some studies suggest that
preeclampsia may be more common in patients with throm- The HELLP (hemolysis, elevated liver function tests, low
bophilia, particularly those with antiphospholipid antibody platelets) syndrome affects 0.10%-0.89% of all live births
syndrome (APLAs). Up to 50% of patients with preeclamp- and is associated with a maternal mortality of 0%-4%.
sia develop thrombocytopenia, the severity of which gener- HELLP and preeclampsia share many clinical features,
ally is related to that of the underlying disease. The although HELLP occurs in a slightly older population (mean
pathogenesis of thrombocytopenia in preeclampsia is not age 25 years). It occurs predominantly in the third trimester,
well understood, but it has been hypothesized that a hypoxic between 28 and 36 weeks of gestation, and, in some cases,
placenta releases antiangiogenic factors, including soluble may occur postpartum, with up to 30% presenting within 48
Flt-1 and soluble endoglin, which impair capillary angiogen- hours of delivery, and even as late as 1 week postpartum.
esis, leading to endothelial dysfunction; and the clinical fea- Generalized edema precedes the syndrome in more than
tures of preeclampsia may evolve in response to endothelial 50% of cases. Approximately 70%-80% of patients with
dysfunction. The levels of sFlt1 and soluble endoglin in preg- HELLP coexist with preeclampsia, which by definition has
nant women are predictive of the severity of preeclampsia. hypertension and proteinuria. The major diagnostic criteria
The observation that endothelial dysfunction and platelet for HELLP include microangiopathic hemolytic anemia,

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levels of serum aspartate aminotransferase exceeding 70 U/L, maydevelop in either the second or third trimesters. TTP
and thrombocytopenia, with a platelet count <100,000/L. presenting during weeks 20-29 gestation is associated
Microangiopathic hemolytic anemia is accompanied by with severe fetal IUGR, and better outcomes have been
schistocytes on the peripheral blood film and an elevated observed when TTP presents <20 weeks or >30 weeks.
LDH; some experts suggest that a minimal LDH of 600 U/dL TTP iscaused by severe deficiency of ADAMTS13, the von
is required for diagnosis. In some cases, HELLP may be dif- Willebrand factor (vWF)cleaving protease, which may be
ficult to distinguish from TTP-HUS. Because many patients congenital (Upshaw-Schulman syndrome) or acquired
with HELLP may present with isolated right upper-quadrant (autoimmune). The hallmark of TTP is microthrombi in
and epigastric pain in the absence of hypertension and pro- small vasculature, which arise as a direct result of accu-
teinuria, patients may be misdiagnosed as having primary mulation of large superadhesive vWF multimers. Micro-
gastrointestinal disease and referred for surgical consider- thrombi lead to thrombocytopenia, microangiopathic
ation. HELLP is associated with significant maternal hemolytic anemia, and neurologic, renal, and central ner-
and fetal morbidity and mortality; therefore, prompt diag- vous system (hypothalamic) end-organ damage. Although
nosis and treatment are essential. In general, if there is congenital TTP accounts for only 5% of adult TTP, it
maternal hemodynamic instability or coagulation profile accounts for 24% of obstetric TTP. The manifestations of
abnormalities or the fetus is at least 32-34 weeks of gestation TTP in pregnant and non-pregnant women are similar,
at the time of presentation, prompt delivery is undertaken and pregnant patients respond equally well to plasma
(Table 3-3). If cesarean delivery is required, red cells, plate- exchange (Table 3-3), as do infants of affected mothers. A
lets, fresh frozen plasma (FFP), or cryoprecipitate (for hypo- major dilemma in the management of TTP is the difficulty
fibrinogenemia) may be necessary during and after delivery. in diagnosis, as overlap with other pregnancy-specific
Although coagulation and platelet abnormalities resolve disorders, such as HELLP, may delay diagnosis and lead to
usually within 48 hours after delivery, thrombocytopenia increased morbidity and mortality. Plasmapheresis is
may continue or become progressive, and thus careful post- the preferred therapy with a response rate reaching 75%.
partum monitoring is essential. If persistent, severe postpar- Corticosteroids have been used, but their effectiveness is
tum, HELLP may require steroids and plasmapheresis. The not established. Antiplatelet agents do not appear to be
offspring of patients with both preeclampsia and HELLP also helpful. TTP relapse and fetal loss in subsequent pregnan-
may become thrombocytopenic, although the thrombocyto- cies is common.
penia is usually mild. Therapy for HELLP and preeclampsia Management: For obstetric TTP, delivery of the fetus and
is directed toward stabilization of the mother, followed by supportive management of the mother is recommended,
expeditious delivery, after which these disorders usually and may include plasma exchange. The effectiveness of cor-
remit within 3-4 days in the majority of patients. HELLP, in ticosteroids is not established. ADAMTS-13 should be mon-
particular, occasionally may worsen or even develop post- itored during pregnancies in patients with non-pregnancy
partum. Prenatal or postnatal corticosteroids have been TTP, and when activity falls to <10%, plasma exchange
suggested in several small, randomized studies to hasten should be initiated.
resolution of the biochemical abnormalities and thrombocy-
topenia associated with HELLP, although these studies have
Hemolytic uremic syndrome
not been powered sufficiently to demonstrate an effect on
maternal or fetal mortality. One should consider the use of The incidence of HUS also is increased in association with
such adjunctive therapies if thrombocytopenia continues to pregnancy. Although some cases of HUS develop near term,
worsen or there is continuing clinical deterioration 5-7 days the majority of cases develop 3-4 weeks postpartum, and
after delivery. their clinical features most closely resemble atypical HUS,
Management: For HELLP, expeditious delivery of the fetus with renal failure as the predominant manifestation. The
and supportive care of the mother is recommended, includ- prognosis of postpartum HUS is poor, with persistent renal
ing transfusion support through delivery, and corticoste- failure in >25% of affected individuals. Although responses
roids and plasma exchange if platelet or coagulation to plasma exchange have been reported, the overall response
abnormalities persist postpartum. rate to this intervention is low; nevertheless, a trial of plasma
exchange is indicated, particularly given the difficulty in dis-
tinguishing TTP and HUS and the potential role of deficien-
Thrombotic thrombocytopenic purpura
cies of complement regulatory proteins in this syndrome
The incidence of TTP is increased during pregnancy. It is (Table 3-3). Treatment is similar to that for obstetric TTP.
estimated that 10%-30% of all adult TTP is obstetric, and There is no consensus on the risk of developing recurrent
7% of all adult TTP has its onset during pregnancy. TTP TTP or HUS in subsequent pregnancies: observational

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60 | Consultative hematology II: womens health issues

Table 3-3 Guidelines for management of microangiopathic hemolytic anemias in pregnancy

Scenario Comments

Preeclampsia, eclampsia
For pregnant women considered at risk for preeclampsia, and those For women with a history of pregnancy complications, screening for
with a previous history of preeclampsia, low-dose aspirin is inherited thrombophilia is not recommended.
recommended throughout pregnancy, starting with the second
Hemolysis, elevated liver function, low platelets (HELLP)
For women with HELLP, delivery of the fetus and supportive care of
the mother, which may include plasma exchange, is recommended.
Thrombotic thrombocytopenic purpura (TTP)
For women with TTP, delivery of the fetus and supportive care of the The effectiveness of steroids is not established.
mother, which may include plasma exchange, is recommended.
Hemolytic uremic syndrome (HUS)
For women with HUS, delivery of the fetus and supportive care of the Observational studies suggest eculizumab may reduce thrombosis and
mother, which may include plasma exchange, is recommended. fetal loss in women with HUS, but it is listed as category C and not
recommended in pregnancy but could be used postpartum. The
effectiveness of steroids is not established.
Acute fatty liver of pregnancy (AFLP)
For women with AFLP, delivery of the fetus and supportive Coagulation support is recommended for liver dysfunction and
management of the mother is recommended. disseminated intravascular coagulation if present.
Disseminated intravascular coagulation (DIC)
For women with DIC, delivery of the fetus and supportive Coagulation support especially if there is bleeding is recommended,
management of the mother is recommended including platelets, FFP, and cryoprecipitate.
Paroxysmal nocturnal hemoglobinuria (PNH)
For women with PNH and past thrombosis or high risk of Observational studies suggest eculizumab may reduce thrombosis and
thrombosis, antepartum and postpartum anticoagulation is fetal loss in women with PNH, but it is listed as category C and is
recommended (see guidelines, next section). not recommended in pregnancy but could be used postpartum.

Adapted from Bates SM et al. Chest. 2012;141(2 suppl):e691Se736S; Woudstra DM, et al. J Thromb Haemost. 2012;10:64-72. Corticosteroids
for HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in pregnancy. Cochrane Database Syst Rev. 2010;9:CD008148; George
JN. Blood. 2010;116:4090-4099; Sanchez-Corral P, Melgosa M. Br J Hematol. 2010;150:529-542; Fesenmeir MF et al. Am J Obstet Gynecol.
2005;192:1416-1419. Vekemans MC et al. Blood Coagul Fibrinolysis. 2015;26:464-466.

studies suggest the risk may be 10-20%, but a recent registry Acquired antithrombin deficiency may also occur and, in
report did not confirm this. rare cases, could lead to thrombosis. Some cases of AFLP and
Management: For obstetric HUS, delivery of the fetus and possibly HELLP may result from fetal mitochondrial fatty
supportive management of the mother is recommended, acid oxidation disorders, most commonly a d eficiency of
which may include plasma exchange. The effectiveness of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase.
steroids is not established. Eculizumab may also be consid- Management: For AFLP, delivery of the fetus and supportive
ered in the postpartum period for atypical HUS. management of the mother, and coagulation support for liver
dysfunction or DIC, if present, is recommended. If deficiency
of anti-thrombin III occurs, ATIII concentrate may be given.
Acute fatty liver of pregnancy

Acute fatty liver of pregnancy (AFLP) usually occurs in the

Disseminated intravascular coagulation
third trimester and affects primarily primiparas, and
although twins are a risk factor, only 1% of cases occur in Disseminated intravascular coagulation (DIC) may occur in
twins. Symptoms include nausea, vomiting, right upper- the third trimester secondary to amniotic fluid embolism,
quadrant pain, anorexia, jaundice, and cholestatic liver dys- retained dead fetus, or abruptio placenta. It may also compli-
function. Hypoglycemia is present in >50% of cases. cate severe preeclampsia/HELLP. DIC is a consumptive coag-
Thrombocytopenia is usually mild, but maternal bleeding is ulopathy characterized by activation of coagulation caused
common due to the accompanying coagulopathy resulting by entrance of thromboplastic or procoagulant substances
from diminished hepatic synthesis of coagulation proteins. into the circulatory system, eg, amniotic fluid. Typically,

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Hematologic health issues inpregnancy | 61

there is consumption of coagulation factors in both intrinsic improved the treatment of PNH. Despite case series suggest-
and extrinsic pathways, prolonging both the PT and APTT, ing eculizumab is safe in pregnancy and prevents PNH-
and consumption of platelets resulting in thrombocytope- induced pregnancy complications, the package insert lists
nia, and presence of breakdown products of fibrin, including eculizumab as category C, with use in pregnancy not estab-
fibrin split products (FSP) and D-dimer. In general, manage- lished, eculizumab could be considered for use postpartum.
ment of DIC is supportive, with platelets, FFP, and cryopre- Management: For pregnant women with PNH, postpar-
cipitate should severe bleeding occur. tum prophylactic- or intermediate-dose LMWH is recom-
Management: For DIC, delivery of the fetus and support- mended, and, in those at high risk for thrombosis (eg, PNH
ive management of the mother is recommended, with plate- clone >50%, prior VTE, or recurrent fetal loss), antepartum
lets, FFP, and cryoprecipitate may be given to replace platelets prophylactic- or intermediate-dose LMWH is recom-
and factors consumed. Frequent monitoring of fibrinogen mended. Use of eculizumab during pregnancy is not estab-
and early replacement of fibrinogen with cryoprecipitate or lished and is classified category C, but eculizumab could be
fibrinogen concentrates are recommended. considered in the postpartum period (Table 3-6).

Paroxysmal nocturnal hemoglobinuria Bleeding disorders in pregnancy

Paroxysmal nocturnal hemoglobinuria (PNH) is a stem cell Postpartum hemorrhage (PPH) is a major cause of morbid-
disorder usually diagnosed in the early 30s. Thus, although ity and mortality in childbirth. Women with an underlying
rare, PNH affects females in their childbearing years. PNH is bleeding disorder are at greater risk for PPH: while several
characterized by hypoplastic anemia, bone marrow failure, single-center studies have reported PPH in up to a third
and hemolysis due to increased susceptibility of red cells to (most with von Willebrand disease), population-based stud-
complement-mediated lysis. The defect is a mutated phospha- ies indicate lower rates of PPH, about 1.5-fold greater than
tidyl inisitol gene (PIG-A), the anchor of the complement women without a bleeding disorder. Bleeding disorders and
regulatory CD55 and CD59 proteins, to the red cell mem- their management in pregnancy, including preferred agents,
brane. This defect results in loss of regulation of the terminal target levels, and dosing, is found in Table 3-4. PPH typically
complex C5b-9, leading to red cell lysis. In the case of the red occurs due to a failure of the uterus to contract after delivery.
cell, the absence of two GPI-linked complement regulatory Primary PPH is defined as an estimated blood loss of >500 mL
genes, CD55 and CD59, increases the sensitivity of red cells to at the time of vaginal delivery, or >1,000 mL at the time of a
activated complement and complement- mediated lysis. In cesarean delivery, and affects 4%-6% of all pregnancies. Sec-
addition to hemolysis, PNH is characterized by arterial and ondary PPH is excessive vaginal bleeding occurring between
venous thrombosis, which may occur due to depletion of 24 hours and 6weeks after childbirth. The most common
nitric oxide which binds circulating free hemoglobin and may causes of PPH in the general obstetric population are uterine
occur at visceral sites, including the inferior vena cava (Budd atony, retained placenta, and genital tract trauma. Women
Chiari), splenic, hepatic, and cerebral veins. Thrombotic risk with inherited bleeding disorders have these same risk fac-
correlates with expression of GPI-linked proteins on the sur- tors, as well as the additional risk factor of their coagulation
face of granulocytes, with thegreatest risk associated with a defect. In the general population, most PPHs are primary,
PNH clone >50%. When PNH occurs in pregnancy, up to 40% with <1% occurring more than 24 hours after delivery. In
end prematurely and only 30% deliver vaginally. Hemolysis women with bleeding disorders, delayed (or secondary) PPH
leads to smooth muscle dystonia, vasculopathy, and endothe- is much more common and has been reported in 20%-25%
lial dysfunction, increasing the risk for premature labor and of women with von Willebrand disease (vWD), 2%-11% of
fetal loss. There is an 8% maternal mortality rate in women hemophilia carriers, and 24% of women with factor XI defi-
with PNH, primarily related to postpartum thrombosis, and a ciency. Risk factors for uterine atony include prolonged
4% fetal mortality rate. It may be difficult to distinguish induced or augmented labor and expectant rather than
thrombotic complications of PNH from thrombotic compli- active management of the third stage of labor. Therefore, in
cations of pregnancy. Because of the high risk of VTE in preg- women with inherited bleeding disorders, these factors
nant women with PNH, at an incidence of 10%, should be minimized to reduce the risk of PPH. Active man-
antithrombotictherapy is recommended postpartum for all agement of the third stage of labor may include the adminis-
pregnant patients, and antepartum prophylaxis is indicated tration of prophylactic uterotonics to increase muscle
for patients with thrombosis-large PNH clones (>50%), prior contractility and controlled traction of the umbilical cord
history of VTE, or recurrent prior late fetal loss. In the during the delivery of the placenta. Hemostatic management
pastdecade, eculizumab, a monoclonal antibody that targets also may reduce the risk of PPH. Factor levels should be
theterminal component of complement, C5, has greatly assessed in the third trimester of pregnancy, and

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62 | Consultative hematology II: womens health issues

Table 3-4 Management of bleeding disorders in pregnancy

Bleeding disorder Factor at delivery Dosing at delivery Target at delivery

von Willebrand disease
Type 1 vWD vWF concentrate 60-80 IU/kg, then 40-60 IU/kg q 8-12 h, then daily 3-5 days vWF:RCo >50 IU/dL
Type 2 vW D (2A, 2B, 2M, 2N) vWF concentrate 60-80 IU/kg, then 40-60 IU/kg q 8-12 h, then daily 3-5 days vWF:RCo >50 IU/dL
Type 3 vW D vWF concentrate 60-80 IU/kg, then 40-60 IU/kg q 8-12 h, then daily 3-5 days vWF:RCo >50 IU/dL
Hemophilia carrier
Hemophilia A carrier FVIII concentrate 25-50 IU/kg IV push, for up to 3-4 days FVIII:C >50 IU/dL
Hemophilia B carrier FIX concentrate 75-100 IU/kg IV, for up to 3-4 days FIX:C >50 IU/dL
Rare bleeding disorder
FI (fibrinogen) deficiency Cryo, FI concentrate 50-100 mg/kg twice weekly, then 3 day postpartum FI >1.0 g/L
FII deficiency FFP, FEIBA FFP 15-20 mL/kg or FEIBA 20-30 IU/kg FII >25 IU/dL
FV deficiency FEIBA FFP 20 mL/kg; FEIBA 75-100 IU/kg FV >15 IU/dL
FVII deficiency FVIIa concentrate FVIIa15-20 g/kg every 3 hours, then taper FVII >40-60 IU/dL
FX deficiency FFP, FEIBA FFP 20 mL/kg; FEIBA 20-30 IU/kg every 48 h FX >10-20 IU/dL
FXI deficiency FFP FFP 15-20 mL/kg; and/or antifibrinolytics FXI >10-20 IU/dL
FXII deficiency NA (no bleeding) NA NA
FXIII deficiency Cryo, FXIII concentrate 10-40 IU/kg, then every 2-3 weeks FXIII >20 IU/dL
Adapted from Nichols WL et al. Haemophilia. 2008;14:171-232; and Kadir R, Chi C, Bolton-Maggs P. Haemophilia. 2009;15:990-1005. It should
be recognized that these represent expert opinion recommendations.
vWD = von Willebrand disease; vWF = von Willebrand factor; vWF:RCo = ristocetin cofactor activity; FVIII:C = factor VIII activity; FIX:C =
factor IX activity; cryo = cryoprecipitate.

prophylactic factor replacement given at delivery to those affected, only 0.1% are symptomatic, but many are unaware
with subtherapeutic levels (Table 3-3). Finally, care must be of their diagnosis. Clinically, the disease is characterized by
taken to minimize genital and perineal trauma to reduce the mucosal bleeding, including menorrhagia, bruising, epi-
risks of both PPH and perineal hematomas. Perineal (or vul- staxis, and postoperative bleeding. There are several variants.
var) hematomas, a rare complication of vaginal birth, occur Type 1 vWD is a partial, quantitative deficiency of vWF, and
with some frequency in women with bleeding disorders and accounts for 70-75% of all vWD cases. Type 2 vWD, account-
contribute to the increased incidence of PPH. In one patient ing for 35% of the disease, consists of four subtypes: type 2A
series, the prevalence of perineal hematoma was much higher is caused by a qualitative defect in vWF in which high
in women with inherited bleeding disorders (1%-6%) as molecular weight vWF (HMW multimers) are reduced,
compared with a reported 0.2% in the general population. resulting in a more severe phenotype; type 2B is character-
Even after discharge from the hospital, women with inher- ized by a gain-of-function mutation resulting in increased
ited bleeding disorders require close follow-up during the affinity and binding of vWF to platelet GP1b, resulting in
postpartum period. In the general obstetric population, the thrombocytopenia and spontaneous platelet aggregation;
median duration of bleeding after delivery is 21-27 days. type 2M is characterized by decreased affinity of vWF for its
A recent case-control study revealed that women with inher- platelet receptor Glycoprotein 1b (GPIb); and type 2N is
ited bleeding disorders have significantly longer postpartum characterized by a loss-of-function mutation in which the
bleeding when compared with controls, even when they vWF binding site for factor VIII (FVIII) is mutated, resulting
receive appropriate hemostatic treatment. In vWD, the in greatly reduced factor VIII, which may be confused for
pregnancy-induced increase in coagulation factor levels
mild hemophilia A. Type 3 vWD accounts for <5% of the
starts to decline 3-7days after delivery and return to pre- disease and is characterized by a severe deficiency in vWF,
pregnancy levels within 7-21 days of delivery. Therefore, resulting in a corresponding deficiency of FVIII. Under the
close postpartum monitoring of women with bleeding disor- regulation of estrogen that occurs in pregnancy, the levels of
ders is recommended for, at minimum, 3weeks. vWF, factor FVIII, and most other clotting factors increase,
generally beginning in the early second trimester and peak-
ing between 29 and 35 weeks. For this reason, a diagnosis of
von Willebrand disease
vWD may be masked if VWF levels are performed when a
vWD is the most common inherited bleeding disorder. patient is pregnant or within 6-8 weeks of delivery, lactating,
Although approximately 1% of the general population is or is using a hormonal contraceptive. Thus, whenever

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Hematologic health issues inpregnancy | 63

possible, the preconception vWF level and bleeding history time of caesarean delivery, and desmopressin may result in
should be established. During pregnancy, most patients fluid retention, life-threatening hyponatremia, and/or sei-
withtype 1 vWD normalize their levels of vWF and FVIII, zures. Recent studies suggest postpartum replacement
although those with more severe disease may not. Given the should aim for VWF levels >50 IU/dL, with some experts
somewhat unpredictable nature of these responses, measure- suggesting a range of 100-200 IU/dL which are observed in
ment of vWF levels should be performed around 34-36 normal pregnant women, as well as postpartum adjuvant
weeks; levels generally remain fairly stable through the tranexamic acid, to reduce PPH. Monitoring for bleeding is
remainder of pregnancy, and thus, levels obtained at this recommended for at least 3 weeks, and, preferably, up to 6
time allow for a delivery plan to be developed. Although lev- weeks postpartum.
els of vWF may increase in patients with type 2 vWD, func-
tional levels may not be significantly enhanced due to the
Hemophilia carriers
production of a functionally defective protein. Levels of vWF
generally do not increase during pregnancy in patients with Postpartum bleeding may occur in 10% hemophilia carriers
type 3 vWD. and may lead to significant blood loss and anemia, in some
In most cases, the physiologic increase in vWF during cases requiring transfusion. The factor level does not predict
pregnancy exceeds the minimum 50 IU/dL vWF level recom- bleeding risk: up to 30% of hemophilia carriers even with
mended for epidural anesthesia and delivery; however, normal factor VIII and IX levels may have high bleeding
inwomen with a severe bleeding history or levels below scores, and up to 15% may be considered to be mild hemo-
50IU/dL at the time of testing, vWF levels should be main- philia. In a small case series of 16 deliveries in five hemo-
tained at delivery at or above 50 IU/dL. This recommenda- philia B carriers, postpartum bleeding was reduced
tion is based on case series and expert opinion, as there are no significantly in those women receiving at least 4 days of factor
randomized trials regarding safe vWF levels for regional IX replacement, as compared with fewer than 4 days of
anesthesia. If epidural anesthesia is used, it is generally judi- replacement. In the hemophilia carrier expecting an affected
cious to remove the catheter as soon as possible after delivery infant, the risk of intracranial hemorrhage is 3-5%. Thus,
is completed. Postpartum, the decline in vWF levels generally although not proven, caesarian delivery is recommended over
occurs over 2-3 weeks, and it may be unpredictable and occa- vaginal delivery to reduce that risk. In high-risk infants, the
sionally precipitous; thus, the period of 3-6 weeks postpar- critical issue is the availability of a multidisciplinary team in
tum is considered a particularly vulnerable time for an obstetric unit with facilities for high-risk deliveries. Of
postpartum bleeding and close follow-up is recommended. course, the problem is that many carriers are not diagnosed
Not only is postpartum bleeding more common in pregnant until after delivery, and even in those who are known carriers,
women with vWD, so too is transfusion requirement, longer an affected infant may not be anticipated if they are not prop-
hospital length of stay, and mortality, which may be up to erly counseled. It should be recognized that pre-conception
1.2%. Several therapeutic options are available. Desmopressin counseling with genotyping is currently available as well as
(1-desamino-8D-arginine vasopressin [DDAVP]) is contra- pre- and postimplantation options, including pre-implantation
indicated with neuraxial anesthesia, as the latter requires fluid genetic diagnosis and postimplantation fetal DNA sex deter-
bolus replacement which is contraindicated with desmopres- mination, chorionic villus sampling, and amniocentesis.
sin. Thus, for patients with type 1 vWD, including those aller- Management: For hemophilia A (or B) carriers with FVIII
gic or unresponsive todesmopressin, and those with type 2 (or FIX) levels <50 IU/dL or severe past bleeding history,
and type 3 vWD,vWF concentrate is recommended and con- recombinant factor VIII (or IX) concentrate is recom-
tinued for up to 3-5 days postpartum, as required by disease mended at the time of neuraxial anesthesia and continued
severity and mode of delivery (Table 3-4). for up to 3-4 days postpartum. In women with hemophilia in
Management: Based on case reports and expert opinion, it whom an affected infant is anticipated, because of the poten-
is recommended that pregnant women with type 1 vWD and tial risk of central nervous system bleeding, caesarean deliv-
vWF <50 IU/dL in the eighth month of pregnancy with a ery should be offered. Vacuum and forceps should be
past severe bleeding history, or unresponsive or allergic to avoided because of the risk of cephalohematoma and intra-
desmopressin, and those with type 2 or 3 vWD receive vWF cranial hemorrhage. A team approach (Table 3-1), including
concentrate for neuraxial anesthesia and for up to 3-5 days the obstetrician, anesthesiologist, and hematologist, and
postpartum. Monitoring for postpartum bleeding is recom- communication regarding mode of delivery and factor
mended for at least 3 weeks and preferably 6 weeks postpar- replacement is critical in managing carriers. Factor VIII con-
tum. vWF concentrate is preferred over desmopressin at centrate is preferred over the use of desmopressin for deliv-
delivery. This is because women commonly receive 1-2 liters ery. Although mild hemophilia A carriers may prefer
of fluid at the time of vaginal delivery and 2-3 liters at the desmopressin for treatment of minor procedures, its use

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64 | Consultative hematology II: womens health issues

is discouraged at delivery. Women commonly receive 1-2 those with afibrinogenemia, but less frequent in those with
liters of fluid at the time of vaginal delivery and 2-3 liters at hypofibrinogenemia or dysfibrinogenemia. Fibrinogen plays
the time of caesarean delivery, and desmopressin at delivery an important role in placental implantation and mainte-
may result in fluid retention and life-threatening hyponatre- nance of placental competency during pregnancy. When
mia and/or seizures. defects in fibrinogen conversion to fibrin occur during preg-
nancy, whether from deficient or defective fibrinogen, pla-
cental separation, miscarriage, spontaneous abortion, and
Rare bleeding disorders
hemorrhage may occur. The high rate of pregnancy compli-
The rare bleeding disorders include inherited deficiencies of cations may be reduced by fibrinogen replacement (Table
coagulation factors I, II, V, VII, X, XI, and XIII, which repre- 3-4). Several experts suggest that fibrinogen replacement
sent 5% of all inherited bleeding disorders. There is a wide should be initiated as early as possible in pregnancy.
spectrum of bleeding severity, from no bleeding to severe Management: For pregnant women with fibrinogen
bleeding, and it i.s difficult to predict bleeding risk. Thus, a <0.5 g/L and previous adverse pregnancy outcomes, prophy-
diagnosis of a rare bleeding disorder may not come to clini- laxis throughout pregnancy with fibrinogen concentrate ini-
cal attention until a woman, even with prior bleeding history, tially 50-100 mg/kg twice weekly adjusted to maintain
experiences postpartum bleeding. In general, risk is related fibrinogen activity >1 g/L to achieve a level of 1.5 g/L during
to factor levels, but not entirely. The key to optimal delivery labor and for 3 days postpartum. For pregnant women with
management is awareness of the diagnosis, testing the appro- thrombotic dysfibrinogenemia or with afibrinogenemia or
priate factor level at the eighth month of pregnancy, and hypofibrinogenemia and other risk factors for VTE, throm-
replacement therapy at delivery for factor deficiency. Because boprophylaxis should be considered.
coagulation factors generally increase during pregnancy, a
diagnosis may be masked during pregnancy and testing
Factor XIII deficiency
should precede pregnancy whenever possible.
In particular, factors I, VII, VIII, vWF, X, XII, and XIII Factor XIII deficiency is a rare disorder, occurring in 1 in 2
increase during pregnancy, whereas factors II, V, IX, and XI million, that is associated with pregnancy loss in over 90%.
show minimal or no increase. In general, fibrinogen levels Long-term prophylaxis is advised in all factor XIII deficient
>1.0 g/L, FII >25 IU/dL, FV >15 IU/dL, FVII >40-60 IU/dL, patients with a personal or family history of bleeding and
FX >10-20 IU/dL, FXI >10-20 IU/dL, and FXIII >30 IU/dL those with FXIII activity <0.1 IU/mL, starting at 10-40 IU/kg
are recommended, respectively, for each deficiency state, at every 2-3 weeks adjusted to maintain a trough XIII activity
the time of delivery. FVII and FXI may require no replace- above 20 IU/dL.
ment therapy (Table 3-4). When possible, preconception Management: For pregnant women with factor XIII defi-
counseling should be provided and genetics and reproduc- ciency, it is recommended the frequency of prophylaxis be
tive choices should be discussed. Although prenatal diagno- increased to 10-40 IU/kg every 2-3 weeks, aiming for a FXIII
sis with chorionic villus sampling and amniocentesis is activity above 20 IU/sL. At the time of delivery, an additional
possible, few obtain it, given the associated 1%-2% fetal loss. dose of 10-40 IU/kg is advised.
As noted, a team approach with a coordinated management
plan optimizes outcomes for affected women.
Management: Based on expert opinion, for rare bleeding Thromboembolism and thrombophilia
factor deficiency states, FFP or factor concentrate to bring fac- inpregnancy
tors to hemostatic levels (Table 3-4) is recommended at the
time of neuraxial anesthesia and for 3-4 days postpartum for Pregnant women are at increased risk for the development
vaginal delivery and up to 5-7 days for caesarean delivery. of thromboembolism. Venous thromboembolism (VTE)
affects 0.66 to 2.22 of 1,000 pregnancies, with a five- to ten-
fold increased relative risk relative to non-pregnant women.
Furthermore, VTE is one of the leading causes of maternal
Fibrinogen abnormalities, including afibrinogenemia, hypo- death in developed countries, accounting for 1.2 to 4.7
fibrinogenemia, and dysfibrinogenemia may be associated deaths per 100,000 pregnancies. VTE is symptomatic in 5-12
with hemorrhagic and thrombotic pregnancy complications, per 10,000 pregnancies and in 3-7 per 10,000 deliveries, for a
including postpartum hemorrhage, spontaneous abortion, seven- to tenfold increased risk for VTE in the antepartum
and placental abruption. Up to 30% of patients with con- period and a 15- to 35-fold increased risk in the postpartum
genital fibrinogen deficiency have thrombotic complications, period. The risk of VTE may be higher in the third than the
most commonly first-trimester abortion: this is common in first and second trimesters, but the increased VTE risk is

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Thromboembolism and thrombophilia inpregnancy | 65

clearly present from the first trimester even before many of protein C resistance in the absence of factor V Leiden (FVL),
the anatomic changes of pregnancy occur. Approximately unexplained by the decrease in free proteins S, also is observed
80% of VTE events are deep venous thrombi (DVT), whereas in some pregnant patients, particularly in the third trimester.
20% are pulmonary embolism: one-third of pregnancy- Furthermore, there is also a decrease in tissue plasminogen
associated DVT and one-half of pulmonary emboli occur activator activity.
after delivery. The relative risk of pulmonary embolism is Management: The anticoagulant of choice in pregnancy is
four- to fivefold greater after caesarean than vaginal delivery. low molecular weight heparin, LMWH (Table 3-5).
The risk of arterial thromboembolism is also increased LMWH is preferred over VKA as well as over subcutaneous
approximately three- to fourfold in pregnant women, reflect- unfractionated heparin (SUH), as (compared with SUH)
ing the hypercoagulable state associated with pregnancy. it is associated with less bleeding risk, more predictable ther-
apeutic response, lower risk of HIT, longer half-life, less
bone density loss, and less local skin hemorrhage. LMWH
Pregnancy-associated venous
(as well as SUH) does not cross the placenta, and numerous
studies have confirmed its use is safe for the fetus.
Pregnancy-associated DVT is more often proximal and mas- At the time of delivery, full-dose LMWH should be dis-
sive than in the nonpregnant setting and usually occurs in the continued at least 24 hours before the induction of labor or
left lower extremity. In contrast, distal DVT occurs with simi- caesarean delivery (or expected time of neuraxial anesthesia)
lar frequency in the left and right lower extremities. The left- and prophylactic dose LMWH should be discontinued at
sided predominance of VTE may reflect compression of the least 12 hours before. Alternatively, the patient can be
left iliac vein between the right iliac artery and lumbar verte- switched to SUH 2-4 weeks before the delivery date to allow
brae. A diagnosis of VTE is difficult in pregnancy because of a for option of an epidural, particularly in case of premature
lack of validation of standard diagnostic studies in this popu- delivery, although a prolonged anticoagulant effect has been
lation. Although an abnormal compression ultrasound (CUS) observed for up to 28 hours with every 12 hour dosing.
is considered sufficient for diagnosis of DVT during preg- LMWH or SUH can be resumed within 4-6 hours after a
nancy, a normal CUS does not reliably exclude DVT because vaginal delivery and 6-12 hours after a caesarean delivery, or
of the low sensitivity for isolated iliac DVT. MRI is the gold longer if peripartum bleeding occurs: in the event that SUH
standard test to diagnose iliac DVT, although an alternative or LMWH are held, sequential pneumatic compression
strategy is negative serial CUS with imaging of the iliac veins. devices should be used. If an epidural is in place, prophylac-
Chest radiography (CXR) is recommended by the American tic LMWH should be resumed no sooner than four hours
Thoracic Society (ATS), the Society of Thoracic Radiology after epidural removal, and full dose LMWH no sooner than
(STR), the ACCP, and ACOG as the first-line radiation-associ- 12 hours after epidural removal.
ated procedure for diagnosis of pulmonary embolism (PE) For pregnant women with acute VTE, adjusted full-dose
unless DVT signs/symptoms are present when CUS should be subcutaneous LMWH is recommended during pregnancy
performed. Lung scintigraphy is preferred if the CXR is nor- and continued or transitioned to a vitamin K antagonist tar-
mal. Computed tomographic pulmonary angiography (CTA) geted to an INR 2.0-3.0 for at least 6 weeks postpartum, for a
is preferred if the screening CXR is abnormal. As D-dimer is minimum total duration of 3 months. VKA is permissible
elevated in pregnancy, it should not be used to exclude PE in during breastfeeding and should be started the evening after
pregnant women. Enhanced hypercoagulability is the major delivery. In patients markedly prothrombotic, with multiple
cause of thrombosis in pregnant women. During pregnancy, risk factors for VTE in the prior 6 months, anticoagulation
hormonal changes, specifically increases in estrogen and pro- may be considered for up to 12 weeks postpartum: the odds
gesterone, lead to a transient hypercoagulable state. This tran- ratio for VTE is 10.8 for up to 6 weeks postpartum, as com-
sient procoagulant state was teleologically important, most pared with the same period one year later, while the odds
likely to protect against miscarriage or fatal hemorrhage at ratio is 2.2 for VTE from 7-12 weeks postpartum, compared
birth. Factor levels that increase during pregnancy include fac- with the same period one year later. While studies do not
tors I (fibrinogen), VII, VIII, X, vWF, and plasminogen activa- conclusively support routine Xa monitoring in pregnant
tor inhibitor (PAI-I and PAI-2), all of which return to normal women requiring full-dose anticoagulation, periodic Xa
beginning 2-3 weeks postpartum. In parallel, a substantial monitoring is reasonable in the obese patient since Xa levels
decrease in free protein S levels occur because of increased lev- fall by 25% in the third trimester as the blood volume rises.
els of C4b binding protein. It is important to recognize that Pharmacokinetics are optimized if dosing for an acute VTEis
protein S levels are as low as 30% in the second trimester and at 1 mg/kg twice daily, with an anti-Xa target of 0.6-1.0 IU/mL,
26% in the third trimester of normal pregnancies, to avoid or at 1.5 mg/kg/d once daily dosing, with an anti-Xa target
misdiagnosis of protein S deficiency. An increase in activated 0.8-1.6 IU/mL, after hospital discharge. For pregnant women

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66 | Consultative hematology II: womens health issues

Table 3-5 American College of Chest Physicians (2012) Guidelines for Antithrombotic Therapy in Pregnancy*

Acute VTE
For pregnant women with acute VTE, adjusted-dose subcutaneous LMWH For pregnant women, LMWH is recommended for
is recommended during pregnancy and continued for at least 6 weeks antithrombotic therapy over adjusted-dose heparin and over
postpartum, for a minimum duration of 3 months. vitamin K antagonists.
For pregnant women receiving adjusted-dose LMWH, LMWH
should be stopped at least 24 hours before induction of labor,
caesarean delivery, or neuraxial anesthesia.
Prior episode of VTE
For pregnant women with prior VTE, postpartum prophylaxis for 6 For women on long-term vitamin K antagonists pre-pregnancy,
weeks with prophylactic- or intermediate-dose LMWH or vitamin adjusted-dose LMWH or 75% of a therapeutic dose of LMWH
Kantagonists targeted at INR 2.0-3.0. is recommended during pregnancy and long-term postpartum.
For pregnant women with low risk of recurrent VTE (single-episode
VTE with transient risk factor unrelated to pregnancy or use of
estrogen), antepartum clinical vigilance and postpartum prophylaxis
with prophylactic or intermediate LMWH or Vitamin K antagonists
targeted to INR 2.0 to 3.0 is recommended.
For pregnant women with moderate to high risk of recurrent VTE
(unprovoked pregnancy- or estrogen-related VTE or multiple
unprovoked VTE on no long-term anticoagulation), antepartum
prophylactic- or intermediate-dose LMWH is recommended.
No prior VTE
High-risk thrombophilia: For pregnant women with no prior VTE For pregnant women with all other thrombophilias (low-risk)
who have homozygous factorV Leiden or the prothrombin 20210A and no prior VTE and no family history of VTE, antepartum
mutation and a familyhistory of VTE [ACOG also Includes combined and postpartum clinical vigilance is recommended. [ACOG
FVL and PTGM heterozygotes or ATIII deficiency and does not require advises postpartum prophylaxis if there is a first-degree relative
a family history of VTE], antepartum prophylaxis with prophylactic- with a history of a thrombotic episode before age 50 years, or
or intermediate-dose LMWH and postpartum prophylaxis for 6 other major thrombotic risk factors, eg, prolonged immobility].
weeks with prophylactic- or intermediate-dose LMWH or vitamin K
antagonists targeted at INR 2.0 to 3.0 is recommended.
Low-risk thrombophilia: For pregnant women with all other For pregnant women undergoing caesarean delivery without
thrombophilias and no prior VTE who have a family history of VTE additional thrombosis risk factors, early mobilization but not
[ACOG defines family history as a first degree relative], antepartum thrombosis prophylaxis is recommended.
clinical vigilance and postpartum prophylaxis with prophylactic-
or intermediate-dose LMWH, or in women who are not protein
C or S deficient, vitamin K antagonists targeted to INR 2.0-3.0 is
For pregnant women with no prior VTE who are known to be homozygous For women at increased risk of VTE after caesarean delivery
for factor V Leiden or the prothombin 20210A mutation, but no family because of the presence of one major and at least two
history of VTE [ACOG advises antepartum prophylaxis even if no family minor risk factors, pharmacologic thromboprophylaxis
history and includes FVL and PTGM heterozygotes or ATIII deficiency], (prophylactic LMWH) is recommended or mechanical
antepartum clinical vigilance and postpartum prophylaxis for 6 prophylaxis (elastic stockings or intermittent pneumatic
weeks with prophylactic- or intermediate-dose LMWH or vitamin K compression) for those with contraindications to
antagonists targeted to INR 2.0 to 3.0 is recommended. anticoagulants while hospitalized.
Adapted from Bates SM et al. Chest. 2012;141(2 suppl):e691Se736S.
INR = international normalized ratio; LMWH = low-molecular-weight heparin; VTE = venous thromboembolism; PTGM = prothrombin gene
mutation (PT20210A).
*See American Congress of Obstetrics and Gynecology (2013) Practice Bulletin (#138) Guidelines.

with hemodynamically unstable PE, tissue plasminogen acti- For pregnant women with prior VTE, postpartum pro-
vator (TPA) has been given if the benefit outweighs the risk, phylaxis for 6 weeks is recommended, with prophylactic or
a reported 6-15% fetal death rate and 8-30% major maternal intermediate-dose LMWH or VKAs targeted to INR 2.0-3.0.
bleeding rate. For pregnant women with low risk of recurrent VTE

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Thromboembolism and thrombophilia inpregnancy | 67

(eg, associated with transient risk factor unrelated to preg- intermediate-dose LMWH is recommended. Antepartum
nancy or use of estrogen), antepartum clinical vigilance and prophylaxis can be considered for pregnant women with
postpartum prophylaxis with low dose or intermediate dose noprior VTE and known ATIII deficiency. Women with ATIII
LMWH or VKAs targeted to INR 2.0-3.0, is recommended. deficiency may also be candidates for anti-thrombin concen-
For pregnant women at moderate to high risk of recurrent trates peripartum. For pregnant women with all otherthrom-
VTE (eg, single unprovoked VTE, pregnancy- orestrogen- bophilias and no prior VTE with a family historyof VTE,
related VTE, or multiple prior unprovoked VTEnot receiv- antepartum vigilance is r ecommended, and postpartum pro-
ing long-term anticoagulation), antepartum prophylaxis phylaxis with prophylactic- or intermediate-dose LMWH or
with prophylactic or intermediate-dose LMWH and post- VKAs targeted to INR 2.0-3.0. For pregnant women with prior
partum prophylaxis for 6 weeks, with low dose or interme VTE, postpartum prophylaxis for 6 weeks with prophylactic-
diate dose LMWH or VKAs targeted to INR 2.0-3.0, is or intermediate-dose LMWH or VKAs targeted to INR 2.0-3.0
recommended. A recent retrospective case series suggests low is recommended.
dose LMWH postpartum prophylaxis may be inadequate
compared to intermediate dose LMWH, and a randomized
Thrombophilia and pregnancy complications
trial is planned to address this issue.
A number of pregnancy complications have been linked to
thrombophilic states. Adverse pregnancy outcomes, how-
Pregnancy and thrombophilia, with and
ever, are not uncommon in the general population, with a
without thrombosis
15% rate of miscarriage and a 5% rate of two or more preg-
Between 20% and 50% of all thromboembolic events that nancy losses. The association between thrombophilia and
occur in pregnant women are associated with a thrombo- pregnancy loss has been confirmed in a number of case-
philic disorder. Published studies indicate the relative risk of control studies for women with thrombophilia, but it has
VTE associated with a thrombophilic disorder in pregnant not been confirmed in the methodologically stronger cohort
women without a family history of VTE is increased about studies. Although a single late fetal loss and severe pre-
34-fold in women who are homozygous for FVL mutation, eclampsia are associated with inherited thrombophilia, fetal
eightfold in women heterozygous for FVL mutation, 26-fold growth restriction and placental abruption are not. In a
for women homozygous for prothrombin G20210A gene meta-analysis of 25 studies, mostly case-control studies,
mutation, and nearly sevenfold in women heterozygous for other than homozygous FVL and homozygous prothrombin
prothrombin G20210A mutation. The positive predictive 20210G, the pooled risk for pregnancy loss was equivocal.
value for pregnancy-associated thrombosis is 1:400-1:500 for More rigorous studies that eliminate patients with previous
the FVL mutation, 1:200 for prothrombin G20210A, and VTE or VTE in pregnancy from the analysis do not support
4.6:100 for double heterozygotes of these mutations, assum- significant risk of recurrent pregnancy loss (Table 3-6).
ing an overall thrombosis rate of 0.66/1,000 pregnancies. Neither has there been any demonstrated association

The positive predictive value was 1:113 for protein C defi- between thrombophilia and preeclampsia, placental abrup-
ciency and 1:2.8 for type I antithrombin deficiency. Impor- tion, or fetal growth restriction.
tantly, regardless of presence of thrombophilia, a positive Management: For women with a history of pregnancy
family history increases the risk for VTE two- to fourfold. complications, screening for inherited thrombophilia is not
Cohort studies in women with protein C deficiency (with no recommended, and, for this group, neither is antithrombotic
past VTE) and a positive family history have a 1.7% risk of prophylaxis recommended. For women with inherited
developing a first antepartum or postpartum VTE, whereas thrombophilia and a history of pregnancy complications,
women who are homozygous carriers for FVL and a positive antithrombotic prophylaxis is not recommended, particu-
family history have a 14% risk. Given the differing absolute larly with the recent results of a randomized trial, the
risks of thrombosis, management should be individualized TIPPS trial, showing lack of benefit with antepartum
based on the type of thrombophilia, presence of homozy- dalteparin in pregnant women with thrombophilia and pre-
gous or heterozygous mutations, history of past VTE or vious placenta-mediated pregnancy complications.
pregnancy complications, and presence or absence of a fam-
ily history of VTE, as well as the presence of additional pro-
Antiphospholipid antibody syndrome
thrombotic conditions (Table 3-5).
Management: For pregnant women with no prior VTE and The strongest evidence of an association between thrombo-
known to be homozygous for FVL or prothrombin 20210GA philia and fetal loss comes from studies in patients with
mutation or a combined heterozygote, and a family history APLAs.A diagnosis of APLA requires both laboratory
of VTE, antepartum prophylaxis with prophylactic- or and clinical criteria. The laboratory criteria require the

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68 | Consultative hematology II: womens health issues

Table 3-6 American College of Chest Physicians guidelines for thrombophilia-related fetal loss

Scenario Comments

Thrombophilia and pregnancy complications

For women with inherited thrombophilia and a history of pregnancy For women with a history of pregnancy complications, screening for
complications, antithrombotic therapy is not recommended. inherited thrombophilia is not recommended.
Antiphospholipid antibody syndrome (APLAs)
For women who fulfill the laboratory criteria for APLA syndrome For women with recurrent early pregnancy loss, 3 pregnancy
andmeet the clinical APLA criteria based on 3 pregnancy losses before 10 weeks of gestation, screening for APLAs is
losses in the first trimester, or one beyond 9 weeks, or a recommended.
morphologically normal neonate before the 34th week due to
eclampsia or severe preeclampsia, antepartum prophylactic- or
intermediate-dose UFH or prophylactic LMWH combined with
low-dose aspirin, 75-100 mg daily, is recommended.
Artificial reproductive technology (ART)
For women developing ovarian hyperstimulation syndrome (OHSS),
there is a 3-fold risk of thrombosis, and LMWH is recommended
for three months postembryo transfer. Prophylaxis is also
appropriate in non-severe OHSS if there high-risk thrombophilia
present (homozygous FVL or PTGM) or low-risk thrombophilia
with a family history of thrombosis.
Paroxysmal nocturnal hemoglobinuria (PNH)
For women with PNH, antepartum and postpartum prophylactic- Eculizumab is listed as category C in pregnancy, and its use is not
or intermediate-dose LMWH is recommended, particularly in established in pregnancy.
those with PNH clones >50%, prior history of VTE, or recurrent
previous late fetal losses.
Heparin-induced thrombocytopenia (HIT)
In pregnant women with HIT, or in those with allergic reaction As safety has not been established in pregnancy, the use of
to heparin or LMWH, antithrombotic therapy with dabigatran (a new oral direct thrombin inhibitor) and
fondaparinux or lepirudin in place of heparin or LMWH is rivaroxaban or apixaban (new oral anti-Xa inhibitors) should be
recommended. avoided.
Adapted from Bates SM et al. Chest. 2012;141(2 suppl):e691Se736S; Bornikova L et al. J Thromb Haemost. 2011;9:1687-1704; Brodsky RA.
Blood. 2009;113:6522-6527.
LMWH = low-molecular-weight heparin; UFH = unfractionated heparin.

presenceof lupus anticoagulant or moderate to high titer proportion of APLA-positive patients experience late fetal
antibodies to immunoglobulin G (IgG) or immunoglobulin loss (after the 10th week of gestation). Inherited thrombo-
M(IgM) anticardiolipin (>99th percentile) or IgG or IgM philia is less strongly associated with pregnancy loss than
-2-glycoprotein I(>99th percentile) on two occasions at APLA. Several randomized studies, none of which were pla-
least 12 weeks apart; and the clinical criteria require >3 first cebo controlled, have examined the effect of treatment of
trimester pregnancy losses, or >1 pregnancy loss at or beyond women with APLAs with aspirin, heparin, or both. These
10 weeks gestation, or >1 premature birth before 34 weeks of studies, which have been small and with heterogeneous crite-
gestation. The importance of -2-glycoprotein I antibodies ria, generally have demonstrated an advantage of aspirin and
is less well established. Correlation of APLAs with fetal heparin over either aspirin or heparin alone, although a
growth restriction or placental abruption remains controver- recent, randomized trial was stopped early when it became
sial. Among women with recurrent fetal loss (>3 miscar- evident that LMWH and aspirin offered no advantage over
riages), 15% have APLA. In some studies, such women aspirin alone, with almost 80% of women in both arms hav-
experience fetal loss at a rate approaching 90% in subsequent ing successful pregnancies.
pregnancies, whereas in other older studies, normal out- Management: For women who fulfill laboratory and cli
comes may occur, even in the absence of treatment. Although nical criteria for APLAs, antepartum prophylactic- or
the majority of fetal losses in normal individuals and patients intermediate-dose unfractionated heparin (UFH) or pro-
with APLA occur early in the first trimester, an increased phylactic LMWH combined with low-dose aspirin, 75-100 mg

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Thromboembolism and thrombophilia inpregnancy | 69

daily is recommended. For women with two or more miscar- disease (see Table 3-7), VKAs ideally should be avoided at
riages but no APLA or thrombophilia, no antithrombotic least during weeks 6-12 of pregnancy. Insufficient data exist
prophylaxis is recommended (Table 3-6). APLA screening is regarding safety or potential teratogenic effects of the new
recommended in women with recurrent pregnancy loss oral anti-Xa and new oral thrombin inhibitors to recom-
(>3miscarriages before 10 weeks or one beyond 9 weeks), or mend their use in pregnancy.
with thrombophilia and recurrent pregnancy loss. Management: In pregnant women, LMWH is the pre-
ferred antithrombotic agent, as discussed above.
Assisted reproductive technology
Oral vitamin K antagonists
Approximately one in six couples experience infertility. In
achieving a subsequent successful pregnancy, assisted repro- Several toxicities of anticoagulant therapy unique to preg-
ductive technology (ART) is employed, primarily, in vitro nancy must be considered when developing anticoagulation
fertilization. ART is coupled with ovarian follicle stimulation treatment approaches. First, the oral VKA warfarin is terato-
by gonadotropins and gonadotropin-stimulating hormones. genic, causing an embryopathy consisting of nasal hypopla-
Despite this, successful pregnancy results in only of 35-40% sia or stippled epiphyses and limb hypoplasia. The frequency
of attempts (cycles). Thrombophilia has been proposed as a of these abnormalities is estimated to be between 5-12%.
potential mechanism in cases of failed reproduction. Case- The teratogenic effects occur primarily following exposure
control studies have indicated a threefold risk of failure in to warfarin during weeks 6-12 (primarily at 6-9 weeks) of
the presence of FVL or APLA, but cohort studies have not pregnancy, whereas warfarin is probably safe pre-conception
substantiated either finding. Furthermore, antithrombotic and during the first 6 weeks of gestation. VKAs used at any
therapy with aspirin or LMWH does not appear to apprecia- time during pregnancy have been associated with rare cen-
bly increase the success rate. On the other hand, ART is asso- tral nervous system (CNS) developmental abnormalities,
ciated with an increased relative risk of VTE in the threefold such as dorsal midline dysplasia and ventral midline dyspla-
range but with a low absolute risk. Arterial events have also sia, leading to optic atrophy. Finally, an increased risk of
been reported. The risk of thrombosis is increased if concur- minor neurodevelopmental abnormalities may occur in the
rent ovarian hyper-stimulation (OHSS) syndrome develops. offspring of women exposed to warfarin during the second
OHSS occurs in a third of cycles and is characterized by and third trimesters, although the significance of these prob-
abdominal pain, bloating, and fluid retention. OHSS is pres- lems is uncertain. Warfarin may cause a dose-dependent
ent in 90% of the arterial events, at a median of 11 days post- anticoagulant effect in the fetus, which may lead to bleeding
embryo transfer, and in ~80% of the venous event, at a at delivery. In at least one series, warfarin was found to
median of 42 days postembryo transfer. Most venous events increase the rate of miscarriage, leading to the recommenda-
occur in the neck or arm veins. tion that heart valve patients receiving VKA during the sec-
Management: Several guidelines advise prophylactic ond trimester of pregnancy should be switched to heparin
LMWH in severe OHSS, withholding LMWH for 12-24 beginning at 36 weeks of pregnancy.
hours before oocyte retrieval then resuming 6-12 hours after Management: In pregnant women, LMWH is the preferred
retrieval and continuing for three months. Prophylaxis is antithrombotic agent.
also appropriate in non-severe OHSS if there is high-risk
thrombophilia (homozygous FVL or PTGM) or low-risk
Heparin-induced thrombocytopenia
thrombophilia with a family history of thrombosis.
Heparin-induced thrombocytopenia (HIT) is an uncom-
mon problem in pregnancy, but with only case series and
Anticoagulation during pregnancy
anecdotal reports, the exact frequency is not known but esti-
A number of scenarios exist concerning the prevention and mated to be between 0.1 and 1% at first UFH (SUH) expo-
treatment of primary and recurrent thrombosis in pregnant sure. Whether platelet counts should be monitored in the
individuals. In general, when anticoagulation is indicated, pregnant patient on LMWH is not established. The mecha-
the agent of choice in pregnancy is LMWH or heparin, based nism by which HIT occurs is binding of antibodies directed
on evidence-based guidelines recently updated by the ACCP against the heparin-platelet-factor 4 complex, so-called hep-
(see the section Bibliography in this chapter). Among arin-platelet factor 4 (HPF4) antibodies, which result in
women with protein C or S deficiency, postpartum VKAs thrombocytopenia, with typically a greater than 50% drop
should be used very cautiously with adequate bridging with below baseline platelet count. The risk of thrombosis is as
LMWH, given the recognized low levels of protein C and S high as 50% in patients with HIT, and, thus, anticoagulation
due to pregnancy alone. In women with valvular heart is critical to prevent thrombosis or pregnancy-related

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70 | Consultative hematology II: womens health issues

Table 3-7 Guidelines for pregnant patients with artificial heart valves

2012 American College of Chest Physician 2014 American Heart Association/American College of
guidelines for pregnant patients with artificial Cardiologyrecommendations for pregnant women with artificial
heartvalves heart valves

Pregnant women with prosthetic heart valves

For women with mechanical heart valves one For women with mechanical heart valves, the following recommendations
of the following anticoagulant regimens is are made:
recommended: Class I (benefit >>> risk) ie, treatment should be given:
1. Adjusted-dose bid LMWH throughout 1. Therapeutic anticoagulation with frequent monitoring is recommended for
pregnancy, adjusted to achieve the all pregnant patients with a mechanical prosthesis.
manufacturers peak anti-Xa LMWH 4 hours 2. Warfarin is recommended in pregnant patients with a mechanical prosthesis
after injection; or to achieve an INR in the second and third trimesters.
2. Adjusted-dose UFH throughout pregnancy 3. Discontinuation of warfarin with initiation of intravenous UFH (with
administered SC every 12 hours in doses aPTT >2 times control) is recommended before planned vaginal delivery in
adjusted to keep the mid-interval aPTT at pregnant patients with a mechanical prosthesis.
least twice control or to attain an anti-Xa
Class IIa (benefit >> risk) ie, treatment is reasonable:
heparin level of 0.350.70 U/mL; or
4. Continuation of warfarin during the first trimester is reasonable for pregnant
3. UFH or LMWH (as above) until the 13th
patients with a mechanical prosthesis if the dose of warfarin to achieve a
week, with substitution by vitamin K
therapeutic INR is 5 mg/day or less after full discussion with the patient about
antagonists until close to delivery when UFH
risks and benefits.
or LMWH is resumed.
5. Dose-adjusted LMWH at least two times per day (with a target anti-Xa level
Pregnant women with prosthetic valves at high risk of 0.81.2 U/mL, 46h post dose) during the first trimester is reasonable
of thromboembolism for pregnant patients with a mechanical prosthesis if the dose of warfarin is
1. For pregnant women with prosthetic heart >5mg/day to achieve a therapeutic INR.
valves at very high risk of thromboembolism 6. Dose-adjusted continuous intravenous UFH (with an aPTT at least two
in whom concerns exist about the efficacy times control) during the first trimester is reasonable for pregnant patients
and safety of UFH or LMWH (eg, older with a mechanical prosthesis if the dose of warfarin is >5mg/day to achieve a
generation prosthesis in the mitral position therapeutic INR.
or history of thromboembolism), vitamin
Class IIb (benefit > risk) ie, additional studies are needed:
K antagonists are suggested throughout
7. Dose-adjusted LMWH at least two times per day (with a target
pregnancy with replacement by UFH or
anti-Xa level of 0.81.2U/mL, 46h post dose) during the first trimester
LMWH (as above) close to delivery.
maybe reasonable for pregnant patients with a mechanical prosthesis
2. For pregnant women with prosthetic valves
ifthedose of warfarin is 5mg/day or less to achieve
at high risk of VTE, additional low-dose
a therapeutic INR.
aspirin, 75-100 mg/d to one of the regimens
8. Dose-adjusted continuous infusion of UFH (with aPTT at least two times
is suggested.
control) during the first trimester may be reasonable for pregnant patients
with a mechanical prosthesis if the dose of warfarin is 5mg/day or less to
achieve a therapeutic INR.
Class III (treatment is not effective, may be harmful):
9. LMWH should not be administered to pregnant patients with
mechanicalprostheses unless anti-Xa levels are monitored 4-6 h after
Adapted from Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. Chest. 2012;141(2 suppl):e691S-e736S; and
Nishimura RA, Otto CM, Bonow RO, et al. JAm Coll Cardiol. 2014;63:24382488.
aPTT = activated partial thromboplastin time; LMWH = low-molecular-weight heparin; SC = subcutaneous; UFH = unfractionated heparin;
VTE = venous thromboembolism.

thrombotic complications. Although up to 50% of cardiac considered to be the first-line therapy (Table 3-6).
surgical patients develop HIT, prospective case series evalu- Fondaparinux does cross the placenta, but the umbilical
ating HPF4 antibody in pregnancy have reported low rates anti-Xa levels are subtherapeutic in the fetus at one-tenth
of HPF4 seroconversion and low rates of thrombocytopenia the maternal level; but it must be stopped to allow safe anes-
(HIT). In pregnant patients with HIT, fondaparinux is thesia and delivery. However, the clinician should be

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Hematologic health issues in thepremenopausal woman | 71

reminded that safety data from first trimester exposure are was 9.2% in women receiving VKAs during pregnancy, with
lacking. Finally, data are insufficient regarding the safety of heparin substituted for VKAs from weeks 6-12, as compared
the new oral anti-Xa inhibitors (eg, rivaroxaban) and oral with a 33.3% risk of thromboembolic complications with
thrombin inhibitors (eg, dabigatran) to recommend their UFH alone throughout pregnancy.
use in pregnancy (Table 3-6). These findings are consistent with other retrospective
Management: In pregnant women with HIT, antithrom- studies demonstrating that VKAs are associated with a lower
botic therapy with fondaparinux in place of heparin or risk of valve thrombosis, maternal thromboembolism, and
LMWH is recommended. systemic emboli. LMWH in lieu of UFH has been used in
pregnant patients with mechanical heart valves, although
valvular thrombosis and maternal thromboembolism occur
Heparin-associated osteoporosis
in up to 22.4% of pregnancies, with the lowest risk, 10-11%,
Prophylactic UFH is associated with a substantial risk of associated with dose-adjusted LMWH, as compared with
osteoporosis and a 2%-3% incidence of vertebral fractures fixed-dose LMWH.
when administered throughout pregnancy. Several reports Management: For pregnant women with prosthetic heart
suggest that substantially fewer instances of osteoporosis valves, guidelines diverge between the 2012 ACCP and the
occur in patients who receive LMWH; however, at least one 2014 AHA/ACC (Table 3-7). AACP advises consideration of
randomized trial found no difference in bone density three approaches: (i) adjusted-dose LMWH throughout
between low-dose UFH and LMWH. pregnancy; (ii) adjusted-dose UFH throughout pregnancy;
Management: In pregnant women, LMWH is recom- or (iii) LMWH or UFH until the 13th week, with substitu-
mended as the preferred antithrombotic agent, as noted tion of VKAs until close to delivery, at which time LMWH or
above. UFH is resumed. For women judged to be at high risk for
thromboembolism, such as older generation prosthesis in
Heparin-associated skin reactions mitral position or previous VTE, VKAs are recommended
throughout pregnancy with replacement by LMWH or UFH
Skin reactions varying from type 1 urticarial eruptions to close todelivery. In women with prosthetic valves at high
type IV delayed hypersensitivity reactions have been reported riskofthrombosis, aspirin, 75-100 mg daily, is also recom-
in 0.3-0.6% of patients receiving heparin. In at least one pro- mended. The 2014 AHA/ACC guidelines advise as a Class 1
spective study of 66 pregnant women, 29% reported pruri- recommendation (ie, benefit >>>risk) the use of VKA in the
tus, local erythema, and less commonly subcutaneous second and third trimesters. For the first trimester, the
infiltrates and pain at the injection site. guidelines stress the complications of VKA for both mother
Management: In pregnant women without signs of a type and fetus are dose-dependent with fewer adverse events
1 reaction, switching to another LMWH preparation is rec- when doses of less than or equal to 5 mg warfarin are used.
ommended. In the approximately one-third in whom skin Consequently, as a Class IIa recommendation (ie, benefit >>
reactions recur after switching from one LMWH prepara- risk), continuation of warfarin is reasonable in the first tri-
tion to another, fondaparinux is recommended. mester when doses less than or equal to 5 mg warfarin are
used; otherwise LMWH should be used in the first trimester.
Artificial heart valves When LMWH is used, adjusted-dose LMWH, based on anti-
Xa levels to a target of 0.8-1.2 IU/mL 4-6 hours after a dose
Without anticoagulant therapy, patients with mechanical
is recommended with monitoring at least every 2 weeks.
heart valves have a high risk of arterial thromboembolism.
Weight-based dosing is not recommended. Although no
Warfarin appears to be more effective than heparin in pre-
guidelines exist for dose-adjustment based on trough anti-
venting valvular thrombosis in these patients. Debate con-
Xa levels, some studies suggest a target anti-Xa level of
tinues, however, as to whether the benefit in prevention of
0.6-0.7 IU/mL.
valvular thrombosis in the mother offsets the risk of
warfarin-induced embryopathy and neurodevelopmental

abnormalities in the fetus. A systematic review of observa-
Hematologic health issues in
tional studies from 1996 to 1997 that assessed outcomes with
thepremenopausal woman
various anticoagulants in women with prosthetic heart
valves found that VKAs were associated with the lowest risk
Bleeding in the premenopausal woman
of valve thrombosis and systemic embolism, with no differ-
ence in fetal wastage and bleeding between groups. The inci- Bleeding disorders in women are an under-recognized and
dence of valve thrombosis was 3.9% and systemic embolism undertreated condition. Hemophilia, the most widely known

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72 | Consultative hematology II: womens health issues

and studied bleeding disorder, is a disease of males. Women, consensus statement published by experts in the field of
however, are as likely as men to have bleeding disorders obstetrics and gynecology and hematology in 2009 states
other than hemophilia and are in fact disproportionately that an inherited bleeding disorder should be considered if
affected by these diseases due to the bleeding challenges of anyof the following indicators are present: (i)HMB since
menstruation and childbirth. Because bleeding disorders in menarche, (ii) family history of a bleeding disorder, or (iii)
women tend to be less severe and specific than hemophilia, it a personal history of one or more additional bleeding
is more difficult for physicians and patients to recognize symptoms.
symptoms and diagnose these conditions. In one national As HMB is such a frequent problem, it would be cost-
survey of 75 women with vWD, the average time from onset prohibitive to screen all women with HMB for underlying
of bleeding symptoms to diagnosis was 16 years. This section bleeding disorders. Identifying patients with either severe or
will review the most common gynecologic manifestations of significant HMB is challenging given that actual measurement
bleeding as well as recommendations for the laboratory eval- of menstrual blood loss is not feasible in clinical practice.
uation and management of women presenting with exces- Therefore, an active area of research has been the develop-
sive bleeding. ment and validation of bleeding assessment tools in this
field. One of the first tools developed was the Pictorial Blood
Assessment Chart (PBAC), first published in 1990. To com-
plete the chart, women compare both the number and degree
The ACOG defines heavy menstrual bleeding (HMB), or of saturation of pads and tampons with those depicted on a
menorrhagia, as menstrual bleeding lasting for >7 days or chart. Lightly stained products obtain a score of 1, moder-
resulting in the loss of >80 cc of blood per menstrual cycle. ately stained a score of 5, and soaked a score of 20. A total
HMB is a common health problem, occurring in as many as score of >100 per menstrual cycle is associated with men-
10%-15% of women during their lifetime, and this excessive strual blood loss of >80 mL (definition of menorrhagia). A
bleeding can lead to iron deficiency and chronic anemia. major limitation of this tool is that it must be completed
Women with HMB have significantly lower perceived gen- prospectively, so results are not available at the time of initial
eral health and have a poorer quality of life in terms of their evaluation. Moreover, completion of the score after the eval-
ability to fully participate in school, work, athletics, and uation may be limited by subjective bias as well as poor com-
social activities. It is well established that HMB is the most pliance. In a study of 226 women who consented to formal
common bleeding symptom among women with bleeding measurement of menstrual blood loss, variables that pre-
disorders, occurring in up to 80%-90% of patients and that dicted blood loss >80 mL were changing a pad or tampon
bleeding disorders are common among women presenting more than hourly, passing clots >1 inch in diameter, and low
with HMB. Therefore, it is imperative that physicians screen ferritin. More recently, a screening tool developed by Philipp
for underlying bleeding disorders when evaluating an ado- et al. may identify women with HMB who are more likely to
lescent or woman with HMB. Up to 11%-16% of women have an underlying bleeding disorder. The tool contains
with heavy menstrual bleeding and a normal gynecologic eight questions in four categories: (i) severity of HMB,
exam will have von Willebrand factor deficiency. A recent (ii)family history of bleeding disorder, (iii) personal history
opinion issued by the Adolescent Health Committee sup- of excessive bleeding, and (iv) history of treatment for ane-
ports screening for vWD in adolescents presenting with mia (Table 3-8). The screen is considered positive if an affir-
severe menorrhagia. It is important to consider that von mative response is obtained in any one of the four categories.
Willebrand factor levels may be affected by stress, inflam- The sensitivity of this tool for underlying hemostatic defects
mation, anemia, pregnancy, oral contraceptives, phase of in adult women is 89%, which increases to 93%-95% with a
the menstrual cycle, and sample processing. Although some serum ferritin level of 20 ng/mL and a PBAC score of >185,
studies suggest that von Willebrand factor levels in healthy respectively. A variety of more general bleeding assessment
individuals are not significantly affected by oral contracep- tools, most modified based on the original Vicenza Bleeding
tive use, further research is needed in this area. Even in the Questionnaire, and including a consensus bleeding assess-
presence of gynecologic disease, such as anovulatory bleed- ment tool set forth by the International Society of Thrombo-
ing in adolescence or fibroids in perimenopause, an under- sis and Haemostasis (ISTH), have been developed. However,
lying bleeding disorder may be an additional contributing the sensitivity and specificity of these instruments in identi-
factor to HMB and should be considered in the evaluation. fying underlying bleeding disorders in women with HMB
In a study of 115 women 13-53 years of age presenting for have not been formally studied. It is important to recognize
evaluation of HMB, adolescents and perimenopausal that because of increased proliferation of the endometrium,
women were just as likely to have an underlying hemostatic menstrual bleeding may be even heavier during anovulatory
defect as women 20-44 years of age. An international cycles. For this reason, HMB in women with inherited

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Hematologic health issues in thepremenopausal woman | 73

Table 3-8 Screening tool for inherited bleeding disorders in women presenting with heavy menstrual bleeding

Screening questions Score

Q1. How many days did your period usually last, from the time bleeding began until it completely 1 = 7 days
stopped? 0 = <7 days
Q2. How often did you experience a sensation of flooding or gushing during your period? 1 = Every or most periods
0 = Never, rarely, or some periods
Q3. During your period did you ever have bleeding where you would bleed through a tampon or napkin 1 = Every or most periods
in 2 hours? 0 = Never, rarely, or some periods
Q4. Have you ever been treated for anemia? 1 = Yes
0 = No
Q5. Has anyone in your family ever been diagnosed with a bleeding disorder? 1 = Yes
0 = No
Q6. Have you ever had a tooth extracted or had dental surgery? 1 = Yes, if had and bled
0 = No
Q7. Have you ever had surgery other than dental surgery? See 7a. below
Q7a. Did you have bleeding problem after surgery? 1 = Yes
0 = No
Q8. Have you ever been pregnant? See 8a. below
Q8a. Have you ever had a bleeding problem after delivery or after a miscarriage? 1 = Yes
0 = No
The screen is considered positive if an affirmative response is obtained in any one of the four categories covered by the eight questions,
including (i) bleeding severity, (ii) family history of bleeding disorder, (iii) personal history of excessive bleeding, and (iv) history of treatment
for anemia. Women with a positive screen should undergo comprehensive hemostatic testing to determine whether they have a bleeding
Scores are adapted from Philipp CS et al. Am J Obstet Gynecol. 2011;204:209.e1-209.e7; and Philipp CS et al. Am J Obstet Gynecol. 2008;198:163.

bleeding disorders often presents at menarche and may be unwilling to use the hormonal preparations recommended
particularly troublesome during the premenopausal years. as first-line therapy.
As a result, more aggressive or combination therapy may be Combined contraceptive agents containing both estro-
required during these time periods. gen and progestin are available in oral, transdermal, and
There are few published trials regarding the management vaginal ring formulations. These agents reduce menstrual
of HMB. In 2007, the NHLBI published guidelines on the loss by inducing changes that thin the endometrium. Sev-
diagnosis, evaluation, and management of vWD. The expert eral studies have demonstrated that combined OCs
panel recommended that the first choice of therapy for HMB increase fibrinogen, prothrombin, and factor VII, and con-
should be combined OCs, with alternative choices including sequently, promote hemostasis. It is unknown whether the
the levonorgestrel intrauterine device, antifibrinolytics, or increase in coagulation factors contributes to the clinical
intranasal desmopressin (DDAVP; Stimate). For women response, but these agents do reduce menstrual blood loss
who desire pregnancy, alternative options for controlling and increase hemoglobin in women with anemia. Addi-
HMB include desmopressin, antifibrinolytics, and vWF con- tional benefits of hormonal management of HMB include
centrate. In women with type 3 vWD or other severe factor cycle regulation, decreased dysmenorrhea, and improve-
deficiencies and severe menorrhagia unresponsive to OC, ment in acne. In a trial of combined contraceptive hor-
levonorgestrel-releasing intrauterine system (LNG-IUS, mones in 14 adolescents with vWD, menstrual blood loss
Mirena), antifibrinolytics, or desmopressin, VWF concen- measured by PBAC decreased in 12 of 14 patients. Although
trates or other concentrates may be considered. In women these agents are generally well tolerated in adolescents,
without bleeding disorders, tranexamic acid, an antifibrinol- there may be hesitancy, particularly in the families of
ytic agent given the first five days of menses, reduces men- young, sexually abstinent adolescents, to use them, and
strual bleeding by 30%-55%. One study in women with time should be allotted for thorough discussion and edu-
bleeding disorders demonstrated that menstrual bleeding cation. Extended cycling or continuous regimens of OCs
was reduced with the use of either intranasal desmopressin can be particularly helpful in reducing menstrual blood
or tranexamic acid. The management of HMB in adolescents loss, especially in the setting of anemia. Breakthrough
presents some additional challenges, as the etiology is often bleeding is a possible adverse effect of these regimens,
multifactorial, and patients or parents may be reluctant or especially in adolescents.

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74 | Consultative hematology II: womens health issues

The LNG-IUS is a progestin-impregnated intrauterine residual follicle after an ovum is extruded. In the acute set-
device that reduces menstrual blood loss by opposing the ting, surgery, tranexamic acid, and clotting factor replace-
estrogen-induced growth of the endometrium. The short- ment have been used to manage hemorrhagic ovarian cysts.
term and long-term efficacy of this device has been demon- OCs, which reduce the likelihood of ovulation and increase
strated in a small cohort of adult women with inherited clotting factors, are used to prevent recurrences (Table 3-9).
bleeding disorders in the United Kingdom. These same Even among women with bleeding disorders but without
investigators have reported on the use of LNG-IUS in five documented hemorrhagic ovarian cysts, there is a high prev-
adolescents with bleeding disorders (16-19 years of age). alence of midcycle pain or mittelschmerz, a phenomenon
Arecent small retrospective study, however, showed that is thought to be associated with bleeding at the time of
IUDswere removed in a significant proportion of women ovulation.
with bleeding disorders because of patient dissatisfaction, Women with bleeding disorders also are diagnosed more
malposition, or expulsion. Larger prospective studies of frequently with endometriosis. In one case-control study,
complication rates and effectiveness of pre-medications endometriosis was reported in 30% of women with vWD as
(eg, nonsteroidal anti-inflammatory agents) or prolonged compared with 13% in the control group. The etiology of
use of anti-fibrinolytics in preventing these complications this phenomenon is unclear, but one hypothesis is that
are needed. Physician-patient discussions regarding this women with HMB are at higher risk of retrograde menstrual
device also require substantial time for education, as patients bleeding (reflux of menstrual blood out of the uterine cav-
often have misperceptions that these devices cannot be ity), which then stimulates the development of endometrial
removed easily once placed, can be placed only in women tissue implants in the fallopian tubes or peritoneal cavity.
who have had children, or perhaps are even limited to those Alternatively, women with bleeding disorders may not be
who have completed their planned childbearing. Patients more likely to develop endometriosis but simply are more
should also be informed of a risk of prolonged spotting likely to present with symptomatic bleeding, or they are
and increased cyst formation. Other progestin-only contra- more likely to experience hemorrhagic cysts that are mis
ceptives, such as depot medroxyprogesterone acetate diagnosed as endometriosis. Similarly, the development of
(Depo-Provera), progestin-only pills, and the Implanon fibroids, polyps, and endometrial hyperplasia may unmask a
subcutaneous implant, also reduce endometrial prolifera- previously subclinical bleeding tendency and cause prob-
tion and therefore menstrual blood loss. Insertion of the lematic bleeding, so that the diagnosis of these conditions
Implanon implant might cause bleeding in a woman with a (but likely not the true frequency) becomes more common
bleeding disorder, and the use of a pre-procedure hemostatic in women with bleeding disorders. As a result of all of these
agent should be considered. manifestations, women with bleeding disorders are more
Management: Females with HMB since menarche or a fam- likely to undergo hysterectomy than their peers and more
ily or personal history of bleeding should be screened for a likely to undergo the procedure at an earlier age.
bleeding disorder. For women with menorrhagia, combined Management: For females who develop hemorrhagic ovar-
OCs containing both estrogen and progestin, are recom- ian cysts, clotting factor replacement alone, or together with
mended first-line therapy (Table 3-9). Alternative approaches tranexamic acid, is recommended for acute management,
include the levonorgestrel-releasing intrauterine system and OCs are recommended to prevent recurrence.
or other progestin-only contraceptives, including Depo-
Provera, progestin-only pills, or subcutaneous implants.
Thrombosis and oral contraceptives in the
Non-hormonal therapies include intranasal desmopressin
premenopausal woman
and antifibrinolytics. For patients with type 3 vWD or other
severe factor deficiencies, vWF or other clotting factor con- Hormonal agents are commonly used by >100 million pre-
centrates during menses may be considered. Based on case menopausal women in the United States in the form of con-
reports and expert opinion, vWF activity (ristocetin) and traceptive agents, which are available in oral, transdermal,
FVIII level >50 IU/dL is adequate for neuraxial anesthesia. and vaginal ring formulations. The most common formula-
tion is the oral combination of estrogen and progestin,
combined OC. Progestin-only agents are as effective as
Hemorrhagic ovarian cysts and endometriosis
estrogen-progestin combination agents and are available in
The second most common reproductive tract bleeding man- oral, intramuscular, intrauterine, and subdermal forms.
ifestation is hemorrhagic ovarian cysts, which occur more Over 40 case-control studies, prospective cohort studies, and
commonly in women with vWD, platelet function defects, randomized trials of women using OC provide estimates of
and rare bleeding disorders than in women without bleeding the risk of VTE to be two- to three-fold greater than in non-
disorders. Ovarian cysts develop when bleeding occurs in the users; although the absolute risk is low, 2-4 per 10,000

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Hematologic health issues in thepremenopausal woman | 75

Table 3-9 Management of menorrhagia, ovarian cysts, and pregnancy in women with von Willebrand disease

Menorrhagia and ovarian cysts in women with vWD Pregnancy in women with vWD

Women with menorrhagia or abnormal vaginal bleeding should have a Women planning pregnancy should have a preconception
full gynecologic evaluation before therapy. evaluation with a hematologist and high-risk obstetrician skilled
in management of vWD.
In an adolescent or an adult woman who does not desire pregnancy Women with vWF levels <50 IU/dL or a history of severe bleeding:
but may desire future childbearing, the treatment of choice for 1. Should be referred to a center with high-risk obstetric
menorrhagia is combined oral contraceptives. capabilities and expertise in hemostasis
Factor replacement may be required for severe acute bleeding or blood 2. Should receive prophylaxis with desmopressin or vWD
loss until the above treatment is effective. concentrate before invasive procedures
3. Should achieve vWF:RCo and FVIII levels of at least
50 IU/dL before delivery and up to 3-5 days afterward
If a woman would otherwise be a suitable candidate for an intrauterine If vWF:RCo and FVIII levels can be monitored and maintained
device, the second choice of therapy for menorrhagia is the >50 IU/dL during labor and delivery, and no other coagulation
levonorgestrel intrauterine system. defects are present, then neuraxial anesthesia may be
considered (recommendation based on case series and expert
For a woman who desires pregnancy, treatment with factor Because coagulation factors return to pre-pregnancy levels within
replacement, desmopression, or antifibrinolytics may be tried to 14-21 days after delivery, health care providers should be in
control menorrhagia. Dilation and curettage is not usually effective close contact with a woman during the postpartum period.
in managing excessive uterine bleeding in vWD.
If all efforts to reduce menorrhagia by factor replacement or hormonal
therapies fail, then surgical intervention may be required. For
women not desiring future pregnancy, uterine ablation, or
hysterectomy. For surgical procedures, factor to maintain vWF or
VIII >50 IU/dL is recommended.
In an adolescent or adult woman with acute hemorrhagic ovarian
cysts, treatment of choice is replacement therapy.
In an adolescent or adult woman who does not desire pregnancy
but may desire future childbearing, the first choice for long-term
prevention of hemorrhagic ovarian cysts should be combined oral
Adapted from James AH et al. Am J Obstet Gynecol. 2009;201:12e1-8; James AH. Thromb Res. 2009;(123)(suppl 2):S124-128; and National
Heart, Lung, and Blood Institute. The Diagnosis, Evaluation, and Management of von Willebrand Disease. Bethesda MD: National Institutes of
Health. NIH Pub. No. 08-5832;2007.
vWF:RCo = ristocetin cofactor activity.

erson-years of OC use. This 2- to 3-fold increased risk is

p ral anticoagulants, such as protein S. Evidence has now
much lower than the 5- to 10-fold increased risk seen during accumulated that the negative influence of OCs on the anti-
pregnancy and the 15-35 fold increased risk during the post- coagulant protein C pathway leads to acquired protein C
partum period. The risk of VTE is highest in the first year of resistance, and this is thought to be a primary mechanism
use, especially in the first three months. Several studies, how- underlying the prothrombotic effect of these agents. Third-
ever, indicate that the VTE risk in heterozygous carriers of generation combined OCs (desogestrel) are associated with
the FVL or prothrombin G20210A is greater than would be higher VTE risk, as are drospirenone-containing prepara-
expected if the risks were additive, that is, 28-50 per 10,000 tions (Table 3-10). Progestin-only contraceptives appear to
woman-years of OC use. In women with protein C or anti- confer lower VTE risk, but there have been no clinical trials
thrombin III deficiency, the absolute VTE risk with OC use is to confirm this. The vaginal ring and the transvaginal patch
reported to be even higher, 400 per 10,000 patient-years of both contain estrogen and are associated with an increased
OC use. risk of thrombosis relative to nonusers.
The increased risk of thrombosis has been attributed to In addition to the small absolute risk of thrombosis with
the estrogen component of contraception preparations. OCs, women may have underlying thromboembolic risk fac-
Estrogen increases procoagulants, such as factor VIII, vWF, tors that augment the contraception-related thrombosis risk.
and fibrinogen, and decreases fibrinolytic activity andnatu- For example, women who have hypertension, smoke, or are

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76 | Consultative hematology II: womens health issues

Table 3-10 Risk of VTE associated with hormonal contraceptives

Contraceptive Odds ratio 95% CI

COC 30 g, desogestrel 7.3 3.30-10.00

COC 30 g, levonorgestrel 3.6 1.75-4.60
Depo-Provera 3.6 0.70-1.50
Transdermal patch* 2.2 0.70-3.80
Vaginal ring* 1.6 1.02-2.37
Progestin-only pills 0.6 0.33-3.41
Levonorgestrel IUD 0.3 0.10-1.26
Adapted from Manzoli L et al. Drug Safety. 2012;35:191-205; Ueng J, Douketis JD. Hematol Oncol Clin North Am. 2010;24:683-694; van
Hylckama Vlieg A et al. BMJ. 2009;339:b2921; Lidegaard O et al. BMJ. 2012;344:e2990; van Hylckama Vlieg A, Helmerhorst FM, Rosendaal
FR. Arterioscler Thromb Vasc Biol. 2010;30:2297-2300; van Vlijmen EF et al. Blood. 2011;118:2055-2061; WHO. Medical eligibility criteria for
contraceptive use. 2008 Update.; Mantha S et al. BMJ. 2012;345:34944.
CI = confidence interval; COC = combined oral contraceptive; IUD = intrauterine device.

>35 years of age have higher risks of myocardial infarction international study reported a possible increase in stroke risk
(MI) and stroke. Diabetes and hypercholesterolemia also in women with hypertension using injectable POCs. Most
increase the risk of MI, while migraines with aura raise the recently, a study from the Netherlands reported a 3.6-fold
risk of stroke. A history of prior VTE or complicated valvular increased risk of VTE in women using Depo-Provera, as
heart disease may increase the risk of contraception-related compared with nonusers, but no increased risk in women
thrombosis. Recently, an increased risk of VTE has been using LNG-IUS. A recent meta-analysis concluded that the
associated with polycystic ovarian syndrome. use of POCs was not associated with an increased risk of VTE
Among users of hormonal contraception, obese women, compared to nonusers. Thus, with a paucity of clinical trials,
smokers, and those with inherited thrombophilia are the many controversies remain regarding optimal contraception
patients at highest risk of VTE. WHO has categorized a in women at risk for thrombosis.
large number of medical conditions according to the level Given the increase in women using artificial reproduction
of risk associated with a variety of contraceptive agents. The technology, clinicians should be aware that in addition to
four categories established by WHO range from no restric- hormonal contraceptive use and pregnancy, another poten-
tions (category 1) to unacceptable health risks (category 4). tial time of increased risk of arterial and venous thrombosis
In 2003, the WHO added a new medical condition to the list for premenopausal women is during ovarian hyper-
of risk states for which OCs are non-preferred contracep- stimulation syndrome, the primary complication of ovarian
tive choicesany known inherited thrombophilia. Women stimulation during artificial reproduction. Thrombosis
who are considered to have an unacceptable level of throm- commonly occurs during the first cycle of treatment and
boembolic risk with OCs may still be candidates for proges- typically in unusual sites such as the jugular and subclavian
tin-only contraceptives. With a few exceptions, the WHO veins. The highest risk is seen in pregnant women with ovar-
classifies all of the risk states described above as category 3 ian hyper-stimulation syndrome requiring hospitalization
or 4 with regard to OCs, but as category 1 or 2 with regard (see the section Anticoagulation during pregnancy in this
to progestin-only products (POC). This remains uncon- chapter for additional information).
firmed with the lack of any trial assessing safety or efficacy Management: For premenopausal females with throm-
of POCs. bophilia seeking contraception, the potential VTE risks
Studies of coagulation factors during POC use have not associated with combined OCs should be weighed against
identified clinically meaningful changes. In case-control the risk of unplanned pregnancy. In the absence of defini-
studies investigating the association between oral POC and tive trials, it is recommended that premenopausal females
VTE, the risk of VTE was not significantly greater in POC with thrombophilia avoid combined OCs. If combined
users as compared with nonusers (Table 3-10), and in a OCs are used, co-administered antithrombotic therapy (eg,
recent meta-analysis there appeared to be no increased risk warfarin or LMWH) may reduce VTE risk. These agents,
of MI with POC use. The latter study included small num- however, are not without risks and their use in this setting
bers of non-healthy POC users. Concern regarding a pos- remains unproven. Alternatively, progestin-only contra-
sible risk of VTE with POC may stem from reports that ceptives or the levonorgestrel intrauterine system may pro-
higher-dose progestins, used for other than contraception vide lower VTE risk than with combined OCs, but this
purposes, have been associated with VTE. Furthermore, an awaits clinical trials. For the present, rather than strictly

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Bibliography | 77

Table 3-11 Safety of medications during pregnancy and breastfeeding

Medication Pregnancy category Breastfeeding

Oral iron: gluconate (ferlecit) B Caution in nursing

Parenteral iron: succrose (venofer) B Caution in nursing
Parenteral iron: dextran (fumoxytol, dexferrum, INFeD) C Caution in nursing
Recombinant erythropoietin (epogen) C Caution in nursing
Folic acid (dietary) A No/minimal risk
Granulocyte colony-stimulating factor (G-CSF) C Caution in nursing
Cyclosporine C Safety unknown, caution advised
Hydroxyurea D Unsafe
Low molecular weight heparin (enoxaparin) B Caution in nursing
Low molecular weight heparin (dalteparin) B Caution in nursing
Low molecular weight heparin (fondaparinux) B Caution in nursing
Corticosteroids (prednisone) D Probably safe
Intravenous immunoglobulin (IVIg) C No/minimal risk
Rho (D) immune globulin (RhoGAM) C Probably safe, caution advised
Romiplostim (Nplate) C Safety unknown, caution advised
Eltrombopag (Promacta) C Safety unknown, caution advised
Azathioprine D Possibly unsafe
Antiplatelet agent (clopidogrel [Plavix]) B Safety unknown, caution advised
Antiplatelet agents (aspirin) D Possibly unsafe
Eculizumab (Soliris) C Caution in nursing
Antithrombin III concentrate (Thrombate) B Safety unknown, caution advised
Factor (VII, VIII, IX, VWF) C Caution in nursing
Recombinant factor (VII, VIII, IX) C Safety unknown, caution advised
Vitamin K antagonists (warfarin [Coumadin]) D (mech valves); X (all other) Caution in nursing
Vitamin K (phytadione) C Safe
For each drug, see package insert for drug-specific recommendations.
Pregnancy category A = Safe for use in pregnancy. Pregnancy category B = Animal studies show no risk or adverse fetal effects but controlled
human 1st trimester studies are not available or do not confirm; no evidence of 2nd, 3rd trimester risk; fetal harm unlikely. Pregnancy
categoryC = Animal studies show adverse fetal effect(s) but there are no controlled human studies OR no animal or human studies
exist; weigh possible fetal risk vs. maternal benefit. Pregnancy category D = Positive evidence of human fetal risk; maternal benefit may
outweigh fetal risk in serious or life-threatening situations. Pregnancy category X = Contraindicated; positive evidence of serious fetal
abnormalities in animals, humans, or both; fetal risks outweigh maternal benefit.

contraindicating OCs in asymptomatic women with findings will evolve to improve care and offer new and better
thrombophilia, particularly those with lower-risk condi- approaches. A commitment by the hematologist to continu-
tions such as factor V Leiden, individual counseling is pre- ally update and stay abreast of new evidence will be critical to
ferred to help women make an informed decision regarding ensure optimal work and interaction by the multidisciplinary
contraception. The absolute risk of VTE is low, and all team, which will translate into the highest quality of care and
combined hormonal contraceptive agents remain extremely best outcomes for women with blood disorders.
safe, with VTE risks much lower than those seen in For reference, Table 3-11 provides some guidance regard-
pregnancy. ing safety of medications during pregnancy and breastfeed-
ing, in the order the medications appear in the text.

This chapter has summarized the most recent evidence-
based guidelines available through the NHLBI, NHF, ACOG, Abdul-Kadir R, McLintock C, Ducloy AS, El-Refaey H, England
ACCP, and WHO to provide optimal care for women with A, Federici AB, Grotegut CA, Halimeh S, Herman JH, Hofer
blood disorders in pregnancy and premenopause. Although S, James AH, Kouides PA, Paidas MJ, Peyvandi F, Winikoff
this compilation is up to date, new therapies and clinical trial R. Evaluation and management of postpartum hemorrhage:

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78 | Consultative hematology II: womens health issues

consensus from an international expert panel. Transfusion. thromboembolism and management of anticoagulation in
2014;54:1756-1768. This is a state-of-the-art document from a women with mechanical prosthetic heart valves. Best Pract
multidisciplinary group on the evaluation and management of Res Clin Obstet Gynaecol. 2014;28:519-536. This provides a
postpartum hemorrhage based on evidence. comprehensive review of thromboprophylaxis of pregnant women,
Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, including those with artificial valves.
Vandvik PO. VTE, thrombophilia, antithrombotic therapy, Middeldorp S. How I treat pregnancy-related venous
and pregnancy: antithrombotic therapy and prevention of thromboembolism. Blood. 2011;118:5394-5400. This study
thrombosis (9th ed.): American College of Chest Physicians reviews drawbacks with D-dimer in diagnosing VTE in pregnancy
evidence-based clinical practice guidelines. Chest. 2012;141 and radiation risks with helical computed tomography scans and
(2 suppl):e691S-e736S. This provides updated guidelines pulmonary angiography, and provides practical therapy for VTE.
for the management of pregnancy-associated thrombosis, Nichols WL, Hultin MB, James AH, Manco-Johnson MJ,
thromboembolism, and pregnancy loss. Montgomery RR, Ortel TL, Rick ME, Sadler JE, Weinstein
Bates SM. Anticoagulation and in vitro fertilization and ovarian M, Yawn BP. Von Willebrand disease (VWD): evidence-
stimulation. Hematology. 2014;379-386. This review provides the based diagnosis and management guidelines. The National
latest evidence for managing women undergoing in vitro fertilization. Heart Lung and Blood Institute (NHLBI) Expert Panel
Committee Opinion No. 580. von Willebrand disease in women. Report (USA). Haemophilia. 2008;14:171-232. This is the first
Committee on Adolescent Health Care; Committee on NHLBI evidence-based clinical guideline for the diagnosis and
Gynecologic Practice. Obstet Gynecol. 2013;122:1368-1373. management of vWD, including recommendations regarding the
Gernsheimer T, James AH, Stasi R. How I treat thrombocytopenia laboratory monitoring and management during pregnancy and the
in pregnancy. Blood. 2013;121:38-47. This review provides a postpartum period.
practical approach to thrombocytopenia in pregnancy. Rodger M. Pregnancy and venous thromboembolism: TIPPS
Goonewardene M, Shehata M, Hamad A. Anemia in pregnancy. for risk stratification. Hematology. 2014;387-392. This
Best Pract Res Clin Obstet Gynaecol. 2012;26:3-24. This review review summarizes findings of the TIPPS study, regarding the
provides an excellent review of all anemias associated with advisability of anticoagulation for thrombotic complications of
pregnancy and suggestions regarding management. pregnancy.
Healthy People 2020; US Government 2000 website. http://2020. Scully M, Thomas M, Underwood M, Watson H, Langley K, Camilleri RS, Clark A, Creagh D, Rayment R, McDonald V,
objectives=4956. Among low-income women the risk of anemia Roy A, Evans G, McGuckin S, Ainle FN, Maclean R, Lester W,
is higher, and thus a goal in this group is reduction of maternal Nash M, Scott R, OBrien P. Thrombotic thrombocytopenic
anemia to 20% or less in the third trimester. purpura and pregnancy: presentation, management, and
James AH, Jamison MG. Bleeding events and other complications subsequent pregnancy outcomes. Blood. 2014;124:211-219. This
during pregnancy and childbirth in women with von is a prospective study of TTP cases from the UK TTP Registry,
Willebrand disease. J Thromb Haemost. 2007;5:1165-1169. This the largest pregnancy-associated TTP cohort, with management
provides data from a national inpatient database of women with suggestions.
postpartum bleeding, including transfusion requirement, length of Venous thromboembolism in women: a specific reproductive health
stay, and mortality in pregnant women with vWD. risk. ESHRE Capri Workshop Group. Hum Reprod Update.
James AH, Kouides PA, Abdul-Kadir R, Edlund M, Federici AB, 2013;19:471-482. This report of the ESHRE Capri Workshop Group
Halimeh S, Kamphuisen PW, Konkle BA, Martinez-Prez, summarizes the VTE risks associated with infertility, combined
McLintock C, Peyvandi F, Winikoff R. Von Willebrand disease hormonal contraception, and hormone replacement therapy, based
and other bleeding disorders in women: consensus on diagnosis on Medline and other database reviews.
and management from an international expert panel. Am J Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell
Obstet Gynecol. 2009;201:12 e1-12 e8. This international panel KL, James AH, Jordan LK, Lanzkron SM, Lottenberg R,
recommended that an inherited bleeding disorder should be Savage WJ, Tanabe PJ, Ware RE, Murad MH, Goldsmith JC,
considered in any female with heavy menstrual bleeding since Ortiz E, Fulwood R, Horton A, John-Sowah J. Management
menarche or a personal or family history of bleeding. of Sickle Cell Disease: Summary of the 2014 evidence-based
James AH, Konkle BA, Kouides P, Ragni MV, Thames B, Gupta S, report by expert panel members. JAMA. 2014;312:1033-1048.
Sood S, Fletcher SK, Philipp CS. Postpartum von Willebrand This special communication provides the 2014 expert panel
factor levels in women with and without von Willebrand disease evidence-based on review of MEDLINE, EMBASE, Cochran,
and implications for prophylaxis. Haemophilia. 2015;21:81-87. CINAHL, TOXLINE, and Scopus databases to address key
This study shows the rapid decline in coagulation levels 3-7 days questions regarding management of sickle cell disease, including
postpartum, and the potential delay up to 3 weeks until pre- stroke prevention, vaso-occlusive crisis, proliferative retinopathy,
pregnancy levels are attained. pulmonary hypertension, use of hydroxyurea, iron chelation, and
McLintock C. Thromboembolism in pregnancy: challenges and hemoglobin targets for preoperative transfusion as well as for long-
controversies in the prevention of pregnancy-associated venous term transfusion therapy.

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