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Hemostasis andThrombosis inObstetrics &GynecologyMichael J. Paidas, MDYale University School of Medicine, New Haven, CT, USA

Nazli Hossain, MBBS, FCPSDow University of Health Sciences, Karachi, Pakistan

Tahir S. Shamsi, MBBS, FRCPath, FCPPNational Institute of Blood Disease and Bone Marrow Transplantation

Karachi, Pakistan and University of Health Sciences, Lahore, Pakistan

Marc A. Rodger, MD, MScOttowa Hospital General, ON, Canada

Jens Langhoff-Roos, MD, DMScRoskilde Hospital, Roskilde and Rigshopitalet, Copenhagen, Denmark

Charles J. Lockwood, MD, MHCMYale University School of Medicine, New Haven, CT, USA

A John Wiley & Sons, Ltd., Publication

iii



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Hemostasis and Thrombosis inObstetrics & Gynecology

i



ii



Hemostasis andThrombosis inObstetrics &GynecologyMichael J. Paidas, MDYale University School of Medicine, New Haven, CT, USA

Nazli Hossain, MBBS, FCPSDow University of Health Sciences, Karachi, Pakistan

Tahir S. Shamsi, MBBS, FRCPath, FCPPNational Institute of Blood Disease and Bone Marrow Transplantation

Karachi, Pakistan and University of Health Sciences, Lahore, Pakistan

Marc A. Rodger, MD, MScOttowa Hospital General, ON, Canada

Jens Langhoff-Roos, MD, DMScRoskilde Hospital, Roskilde and Rigshopitalet, Copenhagen, Denmark

Charles J. Lockwood, MD, MHCMYale University School of Medicine, New Haven, CT, USA

A John Wiley & Sons, Ltd., Publication

iii



This edition first published 2011, C© 2011 by Michael J. Paidas, Nazli Hossain, Tahir S. Shamsi, MarcA. Rodger, Jens Langhoff-Roos and Charles J. Lockwood.

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Library of Congress Cataloging-in-Publication Data

Hemostasis and thrombosis in obstetrics & gynecology / Michael J. Paidas . . . [et al.].p. ; cm.

Other title: Hemostasis and thrombosis in obstetrics and gynecologyIncludes bibliographical references.ISBN 978-1-4051-8399-41. Blood coagulation disorders in pregnancy. 2. Women–Diseases. 3. Hemostasis.

4. Thrombosis. 5. Pregnancy–Complications. I. Paidas, Michael J. II. Title: Hemostasis andthrombosis in obstetrics and gynecology.

[DNLM: 1. Hemostasis–physiology–Handbooks. 2. Blood Coagulation Disorders–Handbooks.3. Pregnancy Complications, Hematologic–Handbooks. 4. Thrombosis–physiopathology–Handbooks. WH 310 H4893 2010]

RG580.B56H33 2010618.3–dc22

2010023429

A catalogue record for this book is available from the British Library.

This book is published in the following electronic formats: ePDF 9781444328349; Wiley OnlineLibrary 9781444328332.

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http://www.wiley.com/wiley-blackwell



Contents

List of Contributors, vi

Preface, vii

Acknowledgments and Dedication, vii

1 Hematologic Changes in Pregnancy, 1

Michael J. Paidas & Nazli Hossain

2 Red Cell Disorders, 12

Tahir S. Shamsi

3 Hemolytic Disease of the Newborn, 28

Tahir S. Shamsi, Nazli Hossain & Michael J. Paidas

4 Maternal and Fetal Thrombocytopenia, 41

Michael J. Paidas & Nazli Hossain

5 Inherited and Acquired Thrombophilia in Obstetrics, 67

Michael J. Paidas, Christina S. Han, Nazli Hossain, and Charles

J. Lockwood

6 Anticoagulant Therapy During Pregnancy and Gynecology, 111

Marc A. Rodger & Genevieve Le Templier

7 Inherited Bleeding Disorders in Obstetrics, 153

Nazli Hossain & Michael J. Paidas

8 Inherited Bleeding Disorders in Gynecology, 161


9 Postpartum Hemorrhage, 167

Nazli Hossain, Jens Langhoff-Roos & Michael J. Paidas

10 Disseminated Intravascular Coagulation, 182


11 Transfusion of Blood and Blood Products in Obstetrics, 195

Tahir S. Shamsi & Nazli Hossain

Index, 216

v



List of Contributors

Christina S. Han, MDClinical instructor, Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology &

Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA

Nazli Hossain, MBBS, FCPSAssociate Professor, Department of Obstetrics and Gynecology, Dow University of Health Sciences,

Karachi, Pakistan

Jens Langhoff-Roos, MD, DMScDepartment of Obstetrics and Gynaecology, Roskilde Hospital, Roskilde, and Department of

Obstetrics, Rigshospitalet, Copenhagen, Denmark

Charles J. Lockwood, MD, MHCMAnita O’Keeffe Young Professor and Chair, Department of Obstetrics, Gynecology and Reproductive

Sciences, Yale University School of Medicine, New Haven, CT, USA

Michael J. Paidas, MDAssociate Professor

Co-Director, Yale Women and Children’s Center for Blood Disorders

Co- Director, National Hemophilia Foundation- Baxter Clinical Fellowship Program at Yale

Division of Maternal Fetal Medicine

Department of Obstetrics, Gynecology and Reproductive Sciences

Yale University School of Medicine, New Haven, CT, USA

Marc A. Rodger, MD, MSc (Epidemiology)Professor of Medicine

University of Ottawa Research Chair in Thrombosis and Thrombophilia Ottowa Hospital General,

ON, Canada

Tahir S. Shamsi, MBBS, FRCPath, FCPPProfessor of Haematology, Consultant Haematologist and Transplant Physician, National Institute of

Blood Disease and Bone Marrow Transplantation, Karachi, Pakistan and University of Health

Sciences, Lahore, Pakistan

Genevieve Le Templier, MD, FRCPCOttawa Hospital, Ottawa Health Research Institute, University of Ottawa, Ottawa, ON, Canada

vi



Preface

Interest in reproductive hemostasis continues to develop among care

providers, basic science and translational researchers across a variety of

disciplines. This phenomenon, it seems, is not a regional, country or

even a continent-specific evolution, but rather a global response. Several

factors have probably contributed to this niche area which is garnering

widespread appeal. International meetings of our respective primary spe-

cialties encourage dialogue with members of other disciplines to tackle

common scientific and clinical dilemmas in women’s health. At many

higher academic institutions, investments in infrastructure to foster a more

‘thematic’ and integrated approach are being promoted. It is obvious to ev-

eryone that communication among colleagues separated by great physical

distances is not as difficult as in the past. Several programs are in place that

support interaction between the developing and the developed countries.

Finally, drugs or biologics, which represent present and future interven-

tions, are definitely global endeavors.

Our goal for this textbook is to provide a contemporary, international,

multidisciplinary approach to common obstetric, gynecologic and hema-

tologic issues, and present the data in a comprehensive, but simplified

manner. This textbook is written for trainees including residents and fel-

lows, seasoned care providers, obstetrician/gynecologists, hematologists,

primary care providers, consultants, and students. We have made delib-

erate attempts to address concerns in the developing and the developed

countries. The chapters are divided according to relevant clinical condi-

tions. We have intended that this textbook be a useful ‘pocket’ reference

for residents, fellows and care providers who might not have immediate

internet access to search a particular question, but need an answer quickly.

This book will provide firm guidelines for obstetricians in the management

of pregnant women in labor and delivery suites.

We have enjoyed writing this book and hope that it stimulates further

collaborative research and discourse directed toward a better understand-

ing of hemostasis and thrombosis issues in the reproduction sciences.

Michael J. Paidas MD

Nazli Hossain MBBS FCPS

vii



Acknowledgments andDedication

There are a few individuals who deserve special mention because they

have influenced my career path that intersects obstetrics, gynecology, the

reproductive sciences, and hematology. I credit Michael J. Haut, MD, who

cultivated my interest in maternal and fetal hematologic disorders dur-

ing residency at Pennsylvania Hospital. Together, we studied aspects of

both maternal and fetal platelet disorders, and he encouraged me to pur-

sue evaluation of in utero fetal platelet function. I have always admired

Fernand Daffos, MD, as a pioneer in many aspects of fetal medicine and

appreciated his encouragement early in my career. Richard L. Berkowitz,

MD, taught me many things, but two lessons in particular have resonated

with me throughout my entire career. Dr. Berkowitz stressed that we, as

physicians, must dedicate ourselves to providing our patients, who entrust

their lives in our hands, with the best care possible. They deserve noth-

ing less than 100% of our best efforts. Secondly, he provided me with

much insight and guidance with his contributions to defining manage-

ment of antenatal alloimmune thrombocytopenia. Perhaps more than any

other individual, I learned from Mary D’Alton, MD, to insist upon car-

rying out good clinical trials in obstetrics to drive practice management

guidelines. For several years, Yale S. Arkel, MD, and Wayne Ku, PhD, gal-

vanized our clinical research efforts focused on the protein C system and

hemostatic derangements associated with pregnancy complications. Both

of them taught me so much about hemostasis and laboratory medicine.

Finally, I owe much to my mentor, collaborator, and colleague, Charles J.

Lockwood, MD, MHCM, who I first met over 25 years ago, for nurturing

my career over such a long period.

Over the years, my patients have served as a daily source of inspiration.

Their courage and determination have been infectious and I wish to thank

them collectively for allowing me to share some aspect of their lives. I wish

to thank my parents, Angela and Nicholas Paidas, who have sacrificed so

much of their life for their children. Finally, I wish to thank my family,

Anne Marie, Nicholas, and Lauren because without their patience, love,

and support, I would not have been able to devote time and energy to this

endeavor and my profession in general.

viii



Acknowledgments and Dedication ix

This book is dedicated to Diana S. Beardsley, MD, PhD, Director of the

Yale Hemophilia Treatment Center. For 24 years, from 1986–2010, Dr.

Beardsley was the face of Pediatric Hemostasis at Yale. She was a superb

physician, brilliant scientist, and tireless advocate and mentor for her fel-

lows, who she mentored during the past three decades. Diana was beloved

by her patients, colleagues, and students. This textbook is a tribute to her

legacy.

Diana S. Beardsley, MD, PhD, December 8, 1947 to March 30, 2010

Michael J. Paidas, MD.

We would like to acknowledge our parents and our families who have

helped us in taking this path; we dedicate this book to mothers who suf-

fered because of ignorance of their disease and taught us how to manage

blood disorders in women.

Nazli Hossain

Tahir S. Shamsi

Marc A. Rodger

Jens Langhoff-Roos

For Nancy, Sarah, John and Billy

Charles J. Lockwood


c01 BLBK321-Paidas August 17, 2010 19:1 Trim: 244mm X 172mm

C H A P T E R 1

Hematologic Changes inPregnancyMichael J. Paidas & Nazli Hossain

Introduction

Normal pregnancy is characterized by profound changes in nearly every

organ system to accommodate the demands of the fetoplacental unit. Ma-

ternal hematological adaptations to the pregnant state are reviewed in this

chapter. The most significant hematological changes are physiologic ane-

mia, neutrophilia, mild thrombocytopenia, increased procoagulant factors,

and diminished fibrinolysis.

This chapter will review the pregnancy-associated changes in plasma

volume, red blood cells, white blood cells, platelets, and coagulation

factors.

Plasma Volume

Plasma volume increases by 10–15% at 6–12 weeks of gestation [1–3],

expands rapidly until 30–34 weeks, after which there is only a modest

rise. The total gain of plasma volume at term averages 1100–1600 mL

and results in a plasma volume of 4700–5200 mL, 30–50% above that

found in nonpregnant women [1, 4]. Plasma volume decreases immedi-

ately postpartum, then increases again 2–5 days after delivery, possibly

because of a simultaneous rise in aldosterone secretion. Plasma volume

then decreases; it is still elevated by 10–15% above nonpregnant levels at

3 weeks postpartum, but is usually at normal nonpregnant levels at

6 weeks postpartum.

During pregnancy, plasma renin activity is typically increased and atrial

natriuretic peptide levels are slightly reduced, suggesting that the increase

in plasma volume represents underfilling due to systemic vasodilatation

and the ensuing rise in vascular capacitance, rather than true blood

Hemostasis and Thrombosis in Obstetrics & Gynecology, 1st edition. By Michael J. Paidas,

Nazli Hossain, Tahir S. Shamsi, Marc A. Rodger, Jens Langhoff-Roos, and

Charles J. Lockwood. Published 2011 by Blackwell Publishing Ltd.

1



2 Hemostasis and Thrombosis in Obstetrics & Gynecology

volume expansion, which would produce the opposite hormonal pro-

file (low plasma renin activity, elevated atrial natriuretic peptide) [5, 6].

Furthermore, the degree of sodium retention is physiologically regulated,

as increasing sodium intake does not produce further volume expansion

[7].

Red Blood Cells

Red blood cell mass begins to increase at 8–10 weeks of gestation and

steadily rises by 20–30% (250–450 mL) above nonpregnant levels by the

end of pregnancy in women receiving iron supplementation [4, 8–11].

Among women not on iron supplements, the red cell mass may only in-

crease by 15–20% [12]. Erythrocyte life span is slightly decreased during

normal pregnancy [13].

Erythropoietin levels increase by 50% in normal pregnancies and vary

according to the presence of pregnancy complications [14]. The increased

plasma erythropoietin induces the rise in red cell mass, which partially

supports the higher metabolic requirement for oxygen during pregnancy

[15]. Mean corpuscular volume decreases during pregnancy and averages

80–84 fL in the third trimester [16].

AnemiaA greater expansion of plasma volume relative to the increase in

hemoglobin mass and erythrocyte volume is responsible for the mod-

est fall in hemoglobin levels (i.e., physiological or dilutional anemia of

pregnancy) observed in healthy pregnant women. The greatest dispro-

portion between the rates at which plasma and erythrocytes are added

to the maternal circulation occurs during the late second to early third

trimester. (Lowest hematocrit is typically measured at 28–36 weeks [16].)

Nearer to term, hemoglobin concentration increases due to cessation of

plasma expansion and continuing increase in hemoglobin mass. Con-

versely, the absence of physiologic anemia appears to be a risk factor for

stillbirth [17].

Determining a good definition of anemia in pregnant women is not

straightforward, given the pregnancy-associated changes in plasma vol-

ume and red cell mass, normal differences in hemoglobin concentrations

between women and men, ethnic variation between white and black

women, and the frequent use of iron supplementation in pregnancy.

The Centers for Disease Control and Prevention has defined anemia as

hemoglobin levels of less than 11 g/dL (hematocrit less than 33%) in the

first and third trimesters and less than 10.5 g/dL (hematocrit less than

32%) in the second trimester [18]. Since hemoglobin and hematocrit



Chapter 1 Hematologic Changes in Pregnancy 3

levels are lower in African-American adults, the Institute of Medicine rec-

ommends lowering of the hemoglobin cutoff level by 0.8 g/dL in this pop-

ulation [19].

Women with hemoglobin values below these levels can be considered

anemic and should undergo a standard evaluation [20]. Sixteen to twenty-

nine percent of pregnant women become anemic in the third trimester

[21].

Severe anemia with maternal hemoglobin below 6 g/dL has been asso-

ciated with reduced amniotic fluid volume, fetal cerebral vasodilation, and

nonreassuring fetal heart rate patterns [22]. Increased risks of prematu-

rity, spontaneous abortion, low birth weight, growth restriction, and fetal

death have also been reported [23]. The administration of lactoferrin to

treat iron deficiency anemia in pregnancy requires further investigation.

Lactoferrin chelates two ferric ions, decreases interleukin-6, thereby de-

creasing hepcidin and increasing ferroportin expression.

Iron RequirementsIn a typical singleton gestation, maternal iron requirements average close

to 1000 mg over the course of pregnancy: approximately 300 mg for the

fetus and placenta and approximately 500 mg, if available, for the expan-

sion of the maternal hemoglobin mass. Two hundred milligrams is shed

through the gut, urine, and skin. Since most women do not have ade-

quate iron stores to handle the demands of pregnancy, iron is commonly

prescribed as part of a prenatal multivitamin or as a separate supplement.

In general, women taking iron supplements have a mean hemoglobin con-

centration that is 1 g/dL greater than that of women not taking supple-

ments. Normal iron indices for pregnancy are listed in Table 1.1.

Folate RequirementsThe increase in red cell mass also necessitates an increased folic acid re-

quirement. In nonpregnant women, the daily folic acid requirement is

50–100 mg/d. However, because folate deficiency is associated with neural

tube defects (and possibly other birth defects) as well as macrocytic ane-

mia, all women of reproductive age are advised to consume 0.4 mg of folic

acid daily [24].

Table 1.1 Normal iron indices during pregnancy

Plasma iron 40–175 �g/dL

Plasma total iron-binding capacity 216–400 �g/dL

Transferrin saturation 16–60%

Serum ferritin 10 �g/dL




Platelet Count

Although platelet counts remain in the normal nonpregnant range in most

women during uncomplicated pregnancies [25], mean platelet counts of

pregnant women may be slightly lower than in healthy nonpregnant

women [26]. Serial platelet counts during uncomplicated pregnancies may

[27] or may not [28] decrease, but the mean values in these groups do not

necessarily reflect both increases and decreases in individual women [29].

The lower limit of normal platelet counts in pregnancy has been reported

to be 106,000–120,000 platelets/�L.

ThrombocytopeniaThe most significant obstetrical consideration concerning platelet physiol-

ogy in pregnancy is thrombocytopenia, which may be related to complica-

tions of pregnancy (e.g., severe preeclampsia, HELLP syndrome), medical

disorders (e.g., idiopathic thrombocytopenic purpura, thrombotic throm-

bocytopenic purpura-hemolytic uremic syndrome), or gestational. Ges-

tational or incidental thrombocytopenia is characterized by mild asymp-

tomatic thrombocytopenia occurring in the third trimester in a patient

without any history of thrombocytopenia (other than in a prior preg-

nancy). It is not associated with maternal, fetal, or neonatal sequelae and

spontaneously resolves postpartum [30–32]. Platelet counts are typically

greater than 70,000/�L.

White Blood Cells

Pregnancy is associated with leukocytosis, primarily related to increased

circulation of neutrophils. The neutrophil count begins to increase in the

second month of pregnancy and plateaus in the second or third trimester,

at which time the total white blood cell counts ranges from 9000 to

15,000 cells/�L [33]. Data from two series reported mean white blood

cell counts of 10,000–16,000 cells/�L in laboring patients, with an upper

level as high as 29,000 cells/�L [34,35]; the mean count increased linearly

with the duration of elapsed labor [35]. The white blood cell count falls to

the normal nonpregnant range by the sixth day postpartum. Dohle bodies

(blue staining cytoplasmic inclusions in granulocytes) are a normal finding

in pregnant women.

In healthy women with normal pregnancies, there is no change in the

absolute lymphocyte count and no significant changes in the relative num-

bers of T and B lymphocytes [36]. The monocyte count is generally stable;

the basophil count may slightly decrease and the eosinophil count may

slightly increase. Normal pregnant women can have a small number of

myelocytes or metamyelocytes in the peripheral circulation.




Coagulation

Normal pregnancy is a prothrombotic state [37–46]. The circulating levels

of several coagulation factors change during pregnancy (Table 1.2):� Protein S activity and free protein S antigen decrease due to estrogen-

induced increases in the complement 4b binding protein and possibly

due to other mechanisms related to the hormonal changes of pregnancy.� Resistance to activated protein C increases in the second and third

trimesters.� Fibrinogen, factors II, VII, VIII, and X increase by 20–200% [47]; von

Willebrand factor also increases.� Activity of the fibrinolytic inhibitors, thrombin activatable fibrinolytic

inhibitor (TAFI), PAI-1, and PAI-2 increases [48].� Factors V and IX remain unchanged and factor XI levels decrease by 30%

[47].

The net effect of these changes is to increase the tendency toward throm-

bus formation, extension, and stability. Normalization of coagulation pa-

rameters varies depending on the factor, but all should return to baseline

by 8 weeks postpartum.

Table 1.2 Hemostatic changes in pregnancy.

Variables (mean ± SD) First tri∗ Second tri∗ Third tri∗ Normal range

Platelet (× 109 1−1) 275 ± 64 256 ± 49 244 ± 52 150–400

Fibrinogen (g/L) 3.7 ± 0.6 4.4 ± 1.2 5.4 ± 0.8 2.1–4.2

Prothrombin complex (%) 120 ± 27 140 ± 27 130 ± 27 70–30

Antithrombin (U/mL) 1.02 ± 0.10 1.07 ± 0.14 1.07 ± 0.11 0.85–1.25

Protein C (U/mL) 0.92 ± 0.13 1.06 ± 0.17 .94 ± 0.2 0.68–1.25

Protein S, total (U/mL) 0.83 ± 0.11 0.73 ± 0.11 0.77 ± 0.10 0.70–1.70

Protein S, free (U/mL) 0.26 ± 0.07 0.17 ± 0.04 0.14 ± 0.04 0.20–0.50

Soluble fibrin (nmol/L) 9.2 ± 8.6 11.8 ± 7.7 13.4 ± 5.2 <15

Thrombin–antithrombin (�g/L) 3.1 ± 1.4 5.9 ± 2.6 7.1 ± 2.4 <2.7

D-dimers (�g/L) 91 ± 24 128 ± 49 198 ± 59 <80

Plasminogen activator

inhibitor-1 (AU/mL)

7.4 ± 4.9 14.9 ± 5.2 37.8 ± 19.4 <15

Plasminogen activator

inhibitor-2 (�g/L)

31 ± 14 84 ± 16 160 ± 31 <5

Cardiolipin antibodies positive 2/25 2/25 3/23 0

Protein Z (�g mL−1)† 2.01 ± 0.76 1.47 ± 0.45 1.55 ± 0.48

Protein S (%)† 34.4 ± 11.8 27.5 ± 8.4

∗First tri, 12–15 weeks; second tri, week 24; third tri, week 35.†First tri, 0–14 weeks; second tri, 14–27 weeks; third tri, 27 weeks or more.

tri, trimester.

Adapted from Bremme [46], table 3, p. 157 and Paidas et al. [51], with permission.




Protein SProtein S (PS) is a vitamin K-dependent glycoprotein with several antico-

agulant functions [49]. In the presence of PS, activated protein C inacti-

vates factor Va and factor VIIIa, resulting in reduced thrombin generation.

PS also serves as a cofactor for protein C enhancement of fibrinolysis. PS

has a direct anticoagulant effect independent of its co-factor function with

activated protein C. It prevents the binding of surface phospholipids with

factors such as Va, Xa, and VIIIa, thereby decreasing the activation of the

factors.

Pregnancy is associated with decreased levels of PS activity and free

PS antigen [44, 50]. The significance and degree of decrease in PS levels

commonly seen in pregnancy has not been vigorously evaluated. To ad-

dress this question, we compared second and third trimester PS levels in

51 healthy women with a normal pregnancy outcome with 51 healthy

women with a poor pregnancy outcome [51]. Protein S levels were sig-

nificantly lower in the second and third trimesters among patients with

adverse pregnancy outcome compared to patients with normal pregnancy

outcome (second trimester 34.4 ± 11.8% versus 38.9 ± 10.3%, respec-

tively; and third trimester 27.5 ± 8.4 versus 31.2 ± 7.4%, respectively).

Resistance to Activated Protein CDuring pregnancy, normal women acquire some degree of resistance to

activated protein C (APC), when measured by the first generation global

assays and tests that measure endogenous thrombin potential [45,52,53].

Factor XFactor X, its activation to FXa and participation in the activation of

prothrombin, is a central element in the generation of thrombin [54]. It

is possible that derangements in the control of factor Xa contributes to

adverse prothrombotic sequelae in pregnancy.

Protein ZProtein Z (PZ) is a 62 kDa vitamin K-dependent plasma protein that serves

as a co-factor for a PZ-dependent protease inhibitor (ZPI) of Factor Xa

[55, 56]. It is a component in the regulation of factor Xa activity in ad-

dition to tissue factor pathway inhibitor [57–59]. PZ deficiency increases

the prothrombotic phenotype in factor V Leiden patients and has been

associated with various adverse clinical sequelae [60–63].

There is a reported increased prevalence of PZ deficiency in patients with

unexplained early fetal loss (10–19 weeks of gestation) and other adverse

pregnancy outcomes [51,64–67]. As an example:� One study reported the odds ratio for fetal loss associated with PZ defi-

ciency was 6.7 (95% CI 3.1–14.8) and noted that the patients with late

fetal loss and recurrent miscarriages had lower PZ levels [65].




� Another study found that women with a variety of adverse pregnancy

outcomes (e.g., intrauterine growth restriction, preeclampsia, preterm

delivery, and antepartum bleeding) had significantly lower PZ levels in

each trimester than women with normal pregnancy outcomes [51]. Pro-

tein Z levels at the twentieth percentile (1.30 mcg/mL) were associated

with an increased risk of adverse pregnancy outcome (OR 4.25, 95% CI

1.5–11.8, sensitivity 93%, specificity 32%).� An inverse correlation was found between anti-protein Z IgM antibody

levels and protein Z concentrations (p = −0.43) in patients with re-

current embryonic loss and PZ deficiency [66]. However, the relation-

ship between PZ antibodies and PZ levels is not straightforward. Anti-

protein Z IgG antibody and anti-protein Z IgM antibody levels were not

correlated with protein Z levels in the entire cohort of patients with

normal and abnormal outcomes. The immunological response to coag-

ulation factors in pregnancy requires further inquiry. A recent meta-

analysis of 28 case-control studies (33 patient cohorts), including 4,218

patients with thrombotic diseases and 4,778 controls, were analyzed

[68]. Low protein Z levels were associated with an increased risk of

thrombosis (odds ratio [OR] 2.90, 95% confidence interval [CI] 2.05–

4.12; p �0.00001). A significant association was found between low

protein Z levels and arterial vascular diseases (OR 2.67, 95% CI 1.60–

4.48; p = 0.0002), pregnancy complications (OR 4.17, 95% CI 2.31–

7.52; p �0.00001), and venous thromboembolic diseases (OR 2.18, 95%

CI 1.19–4.00; p = 0.01). Thus, protein Z deficiency appears to play a role

in thrombotic diseases, including arterial thrombosis, pregnancy compli-

cations and venous thromboembolism.

Activation MarkersActivation markers are often increased in pregnancy. Normal pregnancy is

associated with both increased thrombin activity, increased soluble fibrin

levels (9.2–13.4 nmol/L) and increased thrombin–antithrombin complexes

(3.1–7.1 mcg/L), and fibrinolysis, as evidenced by increased levels of fibrin

D-dimer (91–198 mcg/L) [69].

Summary and Key Points

The major hematological changes during pregnancy are physiologic ane-

mia, neutrophilia, mild thrombocytopenia, increased procoagulant factors,

and diminished fibrinolysis.� Plasma volume increases by 10–15% at 6–12 weeks of gestation, and

then expands rapidly until 30–34 weeks, after which there is only a

modest rise.




� Red blood cell mass begins to increase at 8–10 weeks of gestation and

steadily rises by 20–30% (250–450 mL) above nonpregnant levels by

the end of pregnancy.� A greater expansion of plasma volume relative to the increase in

hemoglobin mass and erythrocyte volume is responsible for the mod-

est fall in hemoglobin levels (i.e., physiological or dilutional anemia of

pregnancy) observed in healthy pregnant women.� The Centers for Disease Control in the United States and Prevention has

defined anemia as hemoglobin levels of less than 11 g/dL in the first and

third trimesters and less than 10.5 g/dL in the second trimester.� Mean platelet counts of pregnant women may be slightly lower than in

healthy nonpregnant women.� The neutrophil count begins to increase in the second month of preg-

nancy and plateaus in the second or third trimester, at which time the

total white blood cell counts ranges from 9000 to 15,000 cells/�L.� There is no change in the absolute lymphocyte count.� The circulating levels of several coagulation factors change during preg-

nancy and contribute to the prothrombotic and antifibrinolytic changes

associated with pregnancy.

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C H A P T E R 2

Red Cell DisordersTahir S. Shamsi

Introduction

Anemia during pregnancy is a well-known risk factor for mother and

fetus [1]. Fetal consequences include risk of intrauterine growth restric-

tion, prematurity, intrauterine death, preterm rupture of membranes and

infection [2]. Maternal consequences of anemia include cardiovascular

symptoms, reduced physical and mental performance, reduced immune

function, tiredness, reduced peripartum blood reserves and finally in-

creased risk of postpartum hemorrhage and need for blood transfusion in

the postpartum period [2–4]. Severe anemia is associated with increased

low birth weight babies, induction rates, operative deliveries, preterm de-

liveries and prolonged labor [5–8].

Anemia

Sixty million pregnant women worldwide are anemic; four million live in

industrialized countries [1]. Worldwide, the prevalence lies between 25

and 50%, reflecting race, socio-economic factors, nutritional habits, med-

ical care, and the frequency of malaria and other parasitic illnesses. In de-

veloping countries, it ranges between 35 and 75%. It is lower in developed

countries, with estimates of 18–20%. The prevalence of iron deficiency

without anemia (which is termed latent iron deficiency) is much higher.

It is most prevalent in pregnant women, infants, and children and is more

common in lower socio-economic groups and in uneducated [3, 9]. Ane-

mia is caused by inadequate diet (mostly insufficient iron but also dietary

deficiencies of folate and vitamin B12); impaired absorption; or blood loss

resulting from hemorrhage or helminths or, in women, from menstru-

ation, childbirth, or repeated pregnancies. Non-nutritional anemia may

be caused by thalassemia and other disorders such as malaria and sickle

Hemostasis and Thrombosis in Obstetrics & Gynecology, 1st edition. By Michael J. Paidas,

Nazli Hossain, Tahir S. Shamsi, Marc A. Rodger, Jens Langhoff-Roos, and

Charles J. Lockwood. Published 2011 by Blackwell Publishing Ltd.

12



Chapter 2 Red Cell Disorders 13

cell disease (SCD). Rarely, hematological malignancies and aplastic ane-

mia present during pregnancy.

Pathophysiology During Pregnancy

Fifty percent of iron deficiency anemia (IDA) occurs after the twenty-fifth

gestational week; it is low during the first trimester and increases during

the second trimester. Pregnancy and lactation stress iron balance. Begin-

ning in the sixth week of pregnancy, maternal plasma volume expands

by approximately 50% during the first and second trimester; whereas the

corresponding increases in red cell mass are only 20–30%. A dilutional

anemia results, so that the lower limit of normal hemoglobin (Hb) concen-

tration is approximately 10.5 g/dL between 16 and 40 weeks of pregnancy.

The increase in red cell mass is due to transfer of iron to the fetus, which

takes place largely in the third trimester, and blood loss during labor, to-

gether they impose a requirement of about 800–1000 mg of iron, so that

iron deficiency frequently arises in mothers with normal or reduced iron

stores if not treated with supplemental iron. It is typically present before

or aggravated by pregnancy. Under normal conditions, up to 10–15% of

nutritional iron is absorbed in the intestine. The main factors influencing

intestinal absorption during pregnancy are the iron demands of the ma-

ternal red cell pool, the fetus and the placenta. Up to 30% of transferrin-

bound iron is released to placental transferrin receptors. There is a positive

feedback mechanism between the placental iron needs and intestinal iron

absorption reaching a maximum rate of 5 mg iron per day. In contrast, iron

need during pregnancy is estimated to be 6–7 mg per day (median need

4.6 mg/d) or 800–1200 mg for the entire pregnancy. As a result, up to

10 years of normal dietary intake is required to replace the loss of iron in-

curred with each pregnancy. A store of more than 500 mg, present in only

20% of menstruating women, is required to avoid iron deficiency during

pregnancy. Thus, the iron deficit grows despite increasing iron absorption.

If iron stores are low before pregnancy, negative iron balance will surely

end in iron deficiency and ultimately IDA.

Anemia is an end result of iron deficiency. The latent and pre-latent

stages of iron deficiency, which produces ineffective erythropoiesis and

defective heme synthesis, are often not detected. Iron absorption is re-

lated to the maternal ferritin concentration, but the influence of maternal

iron stores is limited. Decrease in ferritin concentration of 10 mg/L in-

creases iron absorption by 1.5%. Women with iron deficiency during the

third trimester are able to increase the percentage of iron absorbed above

20–25%. Red blood cell incorporation of iron varies between 76 and 92%,

depending on whether or not iron supplements are given. Recent studies

hemostasis and thrombosis in obstetrics & gynecology · obstetrics & gynecology michael j....

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