INHERITED BLEEDING DISORDERS:
VON WILLEBRAND DISEASE, HEMOPHILIA, & FACTOR XI DEFICIENCY
Pregnant patients with Von Willebrand disease (vWD), hemophilia, or factor XI (FXI)
deficiency should be managed in consultation with a hematologists or other specialist
experienced in this field. All patients with an inherited bleeding disorder, whatever the
type, should have preconception counseling. Decisions regarding childbearing, prenatal
diagnosis and possible termination of an affected pregnancy should be given careful
consideration with ample time to meet consultants who can advise couples and provide
answers to their questions. Also, female members of families with inherited bleeding
disorders should have appropriate testing performed to determine carrier status before
their 1st pregnancies.
Proper planning is extremely important with these patients:
Involve hematology and maternal-fetal consultant early in care.
Plan for L&D on Flow Sheet by entering task (e.g., hematology/anesthesia
prep) on blank line and circling column to be done by early 3rd trimester.
Plan for postpartum by a notation in area 33 of the Flow Sheet: e.g., monitor
for postpartum bleeding. Also add the notation, e.g., fetal bleeding
precautions - circumcision.
VON WILLEBRAND DISEASE (vWD)
vWD is the most common inherited bleeding disorder. Unlike classic hemophilia,
it presents more problems in women than in men. 80% of patients will have a
suspicious history prior to pregnancy and 20% will experience 1st problems with a
vWD is divided into 3 subtypes:
Type I: quantitative deficiency in amount of vW factor (vWF). It is autosomal
Type II: normal amount vWF but qualitative deficiency – several subtypes
dependent on genetic abnormality of vWF molecule. It is almost always
Type III: almost complete deficiency in amount of vWF. Very rare and
associated with severe bleeding. This is autosomal recessive.
Estimates range from 0.8 to 2%. It is worldwide in distribution and found in all
Patients usually have a history of menorrhagia and often report past problems
with epistaxis, mucosal bleeding, easy bruising and hematomas. Petechiae are
not characteristic of vWD. Anemia is common on initial prenatal CBC. The
family history is often notable for postpartum hemorrhage. Approximately 20% of
young women being treated for severe menorrhagia will have vWD.
Patients with a clinical history or family history suspicious for vWD should have
CBC and a von Willebrand’s panel. Because no single test can make the
diagnosis, the panel includes:
APTT – elevated in 40% of patients
Factor VIII activity – decreased in over 50% 0f patients
VWF antigen – usually low in patients with Types I or III; however, it fluctuates
over time and may be normal in pregnancy
Ristocetin cofactor (vWF; RCO) – most sensitive test, decreased in over 80%
Platelet count – should be normal
Bleeding time - is invasive, poorly reproducible, time-consuming, lacks
predictive value and is not sensitive or specific
PFA-100 (Dade Behring Inc., Deerfield, IL), new in vitro test for the detection
of platelet dysfunction, is both sensitive (90-100%) and specific (88-95%) in
the identification of platelet dysfunction associated with vWD
Before conception, women should be offered the opportunity to speak with a
genetic counselor regarding the inheritance of vWD and with a pediatric
hematologist regarding the evaluation of the infant after delivery.
Involve a hematology consultant early in care. Patients with Type I vWD (the
most common type) usually do not have many problems with fertility or
pregnancy. During pregnancy there is a tendency for elevation of factor VIII and
vWF; thus patients with Type I vWD can actually improve. However, women with
Type 3 vWD, Type 2 vWD, or Type 1 vWD with factor VIII levels less than 50
IU/dL, a vWF:RCO less than 50 IU/dL, or a history of severe bleeding should be
referred for prenatal care and delivery to a center where, in addition to specialists
in high-risk obstetrics, there is a hemophilia treatment center or a hematologist
with expertise in hemostasis. Laboratory, pharmacy, and blood bank support is
essential. Before invasive procedures, such as chorionic villus biopsy or
amniocentesis, patients should receive prophylaxis as recommended by the
hematology consultant. The use of desmopressin (DDAVP, l-deamino-8-D-
arginine vasopressin) for prophylaxis is safe during pregnancy.
Because of the possible need for transfusion, women who have not already been
vaccinated should be immunized against hepatitis A and hepatitis B.
Planning for labor and delivery should include consultation with the hematologist
and the anesthesiologist so that appropriate laboratory tests can be obtained and
necessary blood products and medications will be available. Decisions about the
use of prophylactic medications to prevent postpartum hemorrhage will depend,
among other things upon the Type of vWD and the predelivery levels of factor
VIII and vWF:RCO. It is important to remember that fluid retention is a side effect
of both oxytocin and desmopressin.
Plan for L&D on the Flow Sheet by entering task (e.g., hematology/anesthesia
prep) on a blank line and circling the column to be done by early 3rd trimester.
The first line treatment of bleeding problems is with desmopressin. This
synthetic vasopressin acts by stimulating release of vWF from endothelial cells.
It may be given as a nasal spray 150 micrograms in each nostril q 24 hours or IV
at 0.3 micrograms/kg over 30 minutes and can be repeated q 24 hours.
Desmopressin usually increases vWF levels by 3 to 5 fold.
In patients with Type II and III vWD, desmopressin will be ineffective due to
deficiency or absence of vWF. These women will need cryoprecipitate for
The risk for postpartum hemorrhage in women with vWD is variously reported as
25% – 60%; and the risk for perineal hematomas is increased. Also women with
vWD are more likely to have delayed postpartum hemorrhage.
Some consultants recommend weekly phone contact with these patients to
monitor such symptoms. This can be planned by a notation in area 33 of the
Flow Sheet: e.g., monitor for postpartum bleeding q week.
Risks to Mother
Risks include spontaneous abortion, bleeding leading to termination of
pregnancy, and postpartum hemorrhage.
Risks to Infant
There does not appear to be a higher rate of bleeding problems.
Enter to area 31 of Flow Sheet: e.g. von Willebrand disease.
Classic hemophilia A, factor VIII deficiency, is an X-linked disease with an
incidence of 1/10,000; hemophilia B, factor IX deficiency, has an incidence of
1/50,000 – 1/100,000. Therefore, they are primarily male diseases but can occur
in females with abnormal X chromosomes. Caucasians are most often affected.
Genetic counseling should be offered to all patients with a family history. All
pregnant women who are daughters of hemophiliac fathers will be obligate
carriers. If she actually has the disease, all of her sons will be affected and all of
her daughters will be carriers.
Couples in whom the mother is a carrier of hemophilia should consider the
natural conception with or without the use of prenatal diagnosis, especially
assisted conception with donor sperm
Preconception counseling about these options should include a discussion of the
ethical, psychological and financial implications of each option.
Decisions made after genetic counseling should guide further evaluation.
Diagnosis of mothers who are carriers may be based on a reliable family history
or lab testing. Measuring a ratio of factor VIII:C to vWF antigen can diagnosis
carriers if it is 0.5; however, error rates up to 17% may occur. More accurate
testing (up to 96% accuracy) has been shown with a method using restriction
fragment length polymorphisms (RFLPs) within the factor VIII:C gene.
Prenatal diagnosis of hemophilia A (factor VIII deficiency) can be accomplished
by DNA analysis or restriction fragment length polymorphism (RFLP) linked to
the factor VIII gene. Samples for testing can be obtained by chorionic villus
biopsy at 10-12 weeks gestation or amniocentesis (amniocytes) at 16-18 weeks
gestation. These tests are available in only a few specialized laboratories.
Prenatal diagnosis of hemophilia B (factor IX deficiency) is more difficult because
it depends on coagulation assays for factor IX, and fetal blood samples may be
contaminated by factor IX in amniotic fluid. Women at risk for having an infant
with hemophilia should be seen by a fetal-maternal medicine consultant with
experience in genetic counseling and fetal diagnostic procedures.
Monitoring affected patients can be done by following factor VIII coagulation
activity or factor IX assay.
A significant number of patients with hemophilia in the mid-1980’s were exposed
to blood product HIV and hepatitis B, C and became infected. Most of these
patients should be clinically manifest. However, be aware of this potential in
patients from this risk group and test accordingly.
Bleeding episodes during pregnancy (e.g., intramuscular or retroperitoneal
hematoma) can be assessed with ultrasound or CT scan.
Pregnancy is rarely affected and labor may be managed routinely. However,
fetal monitoring with a scalp electrode, operative vaginal delivery, forceps and
vacuum extraction should be avoided.
Women with factor VIII disease can be treated for hematoma and bleeding
episodes as in the non-pregnant patient. Treatments include recombinant factor
VIII:C and DDAVP. For factor IX disease, treatments include: factor IX
concentrate, fresh frozen plasma, and prothrombin complex concentrates.
Circumcision should not be attempted until the neonate has been evaluated for
the disease. Plan this by notation in area 33 of Flow Sheet: e.g., delay
circumcision - hemophilia test.
Discuss dosing and treatment with a consultant.
Enter to area 31 of Flow Sheet: e.g. hemophilia - a family history.
FACTOR XI DEFICIENCY
Factor XI (FXI) is a plasma glycoprotein that participates in the early phase of the
blood coagulation cascade. FXI deficiency, sometimes referred to as hemophilia
C, is an autosomal disorder that occurs with equal frequency in women and men.
It occurs predominantly, though not exclusively, in Jewish populations, especially
of Ashkenazi Jewish descent.
Among Jewish people of Ashkenazi (European) heritage in the United States, the
allele frequency is reported to be somewhere from 8-13.4%. In the non-Jewish
population, factor XI deficiency is observed in approximately 1 per million
Excessive bleeding caused by FXI deficiency can occur at any age, but is usually
associated with surgical procedures. Complications of pregnancy caused by FXI
deficiency are excessive post-abortion and postpartum bleeding in addition to
excessive bleeding with surgical procedures.
FXI should be considered in the differential diagnosis if there is an isolated
prolonged activated partial thromboplastin time (APTT). Severe deficiency
occurs in homozygotes or with FXI levels of less than 0.1-0.15 U/mL. Partial or
mild deficiency is found in heterozygotes whose FXI levels are between 0.2 and
0.7 U/mL. There is controversy about whether FXI levels rise or fall during
The treatment for excessive bleeding caused by factor XI deficiency is fresh
frozen plasma or FXI concentrate. Both of these treatments are associated with
possible untoward side effects and should be administered with consultation from
a hematologist. Small case series suggest that the risk of intrapartum and
postpartum hemorrhage can be reduced in patients with severe or partial FXI
deficiency and a bleeding history with the use of prophylaxis in labor and for
several days after delivery to raise the FXI level to more than 0.7 u/mL. If a
hematologist recommends this, add to area 33: factor XI replacement.
The use of vacuum extraction or rotational forceps delivery should be avoided.
Circumcision should be postponed until the results of FXI levels in the umbilical
cord blood are available. Plan this in area 33 of Flow Sheet: e.g., delay
circumcision – factor XI level test.
Enter to area 31 of Flow Sheet: factor XI deficiency.
Risks to Mother
Risks include post-abortion hemorrhage, postpartum hemorrhage, and bleeding
with surgical procedure.
Risks to Fetus and Neonate
Risks include bleeding associated with operative vaginal delivery, hemorrhage
from circumcision or other surgical procedures.
1 2 34 5 6 7
ACOG Committee on Gynecologic Practice: Von Willebrand’s disease in gynecologic practice.
Committee Opinion, No.263, Dec 2001. Obstet Gynecol, 98:1185-1186, 2001.
Franhini M: Haemostasis and pregnancy. Thrombo Haemost, 95:401-413, 2006.
James A: Von Willebrand disease. Obstet Gynecol Surv, 61:136-145, 2006.
Kadir RA: Women and inherited bleeding disorders: pregnancy and delivery. Semin Hematol,
36 (3 Suppl):28-35, 1999.
Oyesiku JO, Turner CF: Reproductive choices for couples with haemophilia. Haemophilia,
David AL, Paterson-Brown, Letsky EA: Factor XI deficiency presenting in pregnancy: diagnosis
and management. BJOG, 109:840-843, 2002.
Kadir RA, Lee CA, Sabin CA, et al: Pregnancy in women with von Willebrand’s disease or
factor XI deficiency. Br J Obstet Gynaecol, 105:314-321, 1998.