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Case 32. Postpartum Hemorrhage Postpartum Hemorrhage Posted 8-4-04 Key Points ● ● ● ● Identifying the cause of postpartum hemorrhage can have important implications for management of the neonate. Hemophilia A is an X-linked genetic disorder is a rare cause of postpartum hemorrhage. It is caused by mutations in the F8 gene which encodes the factor VIII protein. About 10% of Hemophilia A carrier females are at risk for bleeding, although symptoms tend to be mild in comparison to affected mal
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  Case 32. Postpartum Hemorrhage Postpartum Hemorrhage Posted 8-4-04 Key Points ●   Identifying the cause of postpartum hemorrhage can have important implications for management of the neonate. ●   Hemophilia A is an X-linked genetic disorder is a rare cause of postpartum hemorrhage. It is caused by mutations in the F8  gene which encodes the factor VIII protein. ●   About 10% of Hemophilia A carrier females are at risk for bleeding, although symptoms tend to be mild in comparison to affected males. ●   Historically, some individuals with hemophilia A received blood and blood components infected with HIV as a result of poor screening of the blood supply. Feelings of mistrust in families with hemophilia A toward the blood banking system, and perhaps even the medical community, still exist as a result of this experience. Learning Objectives Participants will be able to: ●   Evaluate the likelihood that a female with postpartum hemorrhage could have hemophilia A; ●   Determine a testing strategy for hemophilia A among family members at risk; ●   Explain in general terms how female carriers can have symptoms of an X-linked condition. Family History Issues X-linked recessive diseases are characterized by a family history of affected males on the mother's side. Typically, only males are affected, with females transmitting the disease; however, mild clinical findings can sometimes be seen in female carriers.With hemophilia A, one-third to one-half of males have no family history of this condition. In such cases, several possibilities regarding the mother's carrier status and the carrier risks of extended family members need to be http://www.genetests.org/servlet/access?id=888889...ename=/tools/cases/postpartumHem-32/content.html   (1 of 9) [3/5/2009 9:17:49 AM]  Case 32. Postpartum Hemorrhage considered. Possibilities include the following: ●   The proband has a new (de novo) mutation; in this case, the mother would not be a carrier and other relatives would not be at risk. ●   The proband inherited the mutation from his mother, who carries a de novo mutation. In this case, his mother would be at risk of having additional affected children, but other relatives on her side of the family would not be at risk. ●   The proband inherited the mutation from his mother, who inherited it from her mother; in this case, she and other female relatives on her side of the family are at risk of having affected children. If there are few male children on this side of family, this could explain the negative family history. Red Flags Untreated hemophilia A is characterized by prolonged bleeding after injuries, tooth extractions, or surgery; renewed bleeding after initial bleeding has stopped; and in severe cases, hemophilia A causes spontaneous joint bleeding. [Arun & Kessler 2001]. Some female carriers of hemophilia A experience mild bleeding problems; these women often have a history of heavy menstrual periods (menorrhagia) and prolonged bleeding after tooth extractions. Case 32. A 30-Year-Old Woman with Postpartum Hemorrhage A 30-year-old woman, Mrs. P, experiences a severe postpartum hemorrhage approximately 24 hours after delivering her first child, a boy. She is told she may have a bleeding tendency, which would require careful monitoring in any future pregnancy but is unlikely to cause other medical problems. In the course of evaluating the patient, you learn that she had difficulty with prolonged bleeding after her wisdom teeth were extracted. You obtain a family history and learn that a male first cousin, Joe, had bleeding problems http://www.genetests.org/servlet/access?id=888889...ename=/tools/cases/postpartumHem-32/content.html   (2 of 9) [3/5/2009 9:17:49 AM]  Case 32. Postpartum Hemorrhage and died from complications of AIDS at age 25 years. You ask Mrs. P to see if she can find Joe's medical records, and Mrs. P learns that her aunt kept copies of them. Review of Joe's medical records confirms that he had a diagnosis of severe hemophilia A and AIDS, secondary to receiving blood products. Joe was initially diagnosed with hemophilia A based on testing that showed he has less than 1% of normal factor VIII clotting activity. Clinical Care Issues Identifying the cause of postpartum hemorrhage Most cases of postpartum hemorrhage are due to readily diagnosable obstetric problems, some are due to acquired coagulopathies, and a small number are due to inherited coagulopathies (<1%). Thus, in general, the likelihood of a genetic cause for this problem is low and other more likely causes should be considered first. Among genetic causes, mild von Willebrand disease, an autosomal dominant disorder, is much more common than hemophilia A, and may also present with low non-pregnant factor VIII levels (see MedlinePlus: von Willebrand disease). Physicians should be particularly suspicious of a clotting disorder when confronted when a new mother is readmitted with a late (>24 hours after delivery) postpartum hemorrhage. If the mother is a symptomatic carrier (i.e., has baseline factor VIII clotting activity below 35%), she will be somewhat protected by the natural rise of factor VIII clotting activity during pregnancy, which may even double by the end of the third trimester. Post-partum, however, factor VIII clotting activity returns to baseline within 24-48 hours, and delayed bleeding may ensue. Symptomatic carriers may or may not have a history of heavy menstrual periods (menorrhagia) since menarche but more often than not will have had several days of oozing after wisdom tooth extraction; major injuries or other surgeries are less frequently encountered to challenge their hemostatic systems.Once Mrs. P's history of a cousin with hemophilia A is confirmed, the likelihood of hemophilia A as the cause of her late postpartum hemorrhage increases. Approximately 10% of women who are carriers of hemophilia A experience postpartum hemorrhage. What is hemophilia A and how is it diagnosed? http://www.genetests.org/servlet/access?id=888889...ename=/tools/cases/postpartumHem-32/content.html   (3 of 9) [3/5/2009 9:17:49 AM]  Case 32. Postpartum Hemorrhage ●   Hemophilia A is characterized by deficiency in factor VIII. Hemophilia A is typically diagnosed by measuring factor VIII clotting activity. ●   Severity of the condition ranges from mild (5-35% of normal factor VIII clotting activity) to severe (<1% factor VIII clotting activity). ●   Hemophilia A is caused by mutations in the F8  gene on the X chromosome. Molecular genetic testing of the F8  gene can identify disease-causing mutations in up to 95% of individuals with hemophilia A, depending on the test method used. Carrier status can also be evaluated by genetic testing. ●   Approximately 10% of females who are carriers of hemophilia A have factor VIII clotting activity <35%. Factor VIII clotting activity is unreliable in the detection of carriers because Factor VIII clotting activity in plasma is increased with pregnancy, oral contraceptive use, aerobic exercise, and chronic inflammation and is approximately 25% lower in individuals of blood group O than in those of other blood groups (i.e., A, B, or AB). Genetic explanation for hemophilia A symptoms in a female Bleeding abnormalities occur in female carriers of hemophilia A as a result of X-chromosome inactivation . In any given cell in a female's body, only one X chromosome is actively transcribed. X-chromosome inactivation occurs early in development at random, so that only one of the two X's is active in each cell. Because X-chromosome inactivation is random, about half of the cells of a female have the paternal X chromosome as the active X and about half have the maternal X chromosome as the active X. A woman who is a carrier for hemophilia A has one X chromosome with an F8  mutation and one chromosome with the normal F8  gene. With X inactivation, she still has the normal F8  gene active in half her cells. However, in some female carriers, X-chromosome inactivation may by chance affect a higher proportion of the X chromosomes with the normal F8  gene in the tissue producing factor VIII (the liver). If this asymmetric X-chromosome inactivation occurs in the liver, the carrier may have a factor VIII activity level below normal and thus experience bleeding problems. These symptoms are generally mild compared to the bleeding problems of the affected male. Risk Assessment Role of family history in assessing risk http://www.genetests.org/servlet/access?id=888889...ename=/tools/cases/postpartumHem-32/content.html   (4 of 9) [3/5/2009 9:17:49 AM]
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