Case Challenges

A pregnant 40-year-old with possible hemophilia carrier status

A 40-year-old woman who was 9 weeks pregnant with her first child presented for evaluation of easy bruising. 


Approximately 16 years earlier, she planned to have tonsillectomy and underwent screening coagulation studies. Those studies reportedly were normal except for a prolonged activated partial thromboplastin time (aPTT) of 53 seconds.


She then underwent further workup and reportedly was found to have a positive lupus inhibitor, although this apparently had been intermittently positive on subsequent testing.


Tim McCarthy, MD 

Tim McCarthy

Clinically, she reported a history of heavy menstrual periods when she was younger. Menses began at age 12 years and would last approximately 7 days. During this time, she experienced heavy bleeding that required change of products every hour. Her periods slowed as she aged, and they currently last approximately 4 days.


She also reported a history of easy bruising, although she denied any history of other excessive bleeding. She underwent hemorrhoid surgery 4 years prior with no significant bleeding 
complications.


In addition, 3 weeks before presentation, she fell from a horse and suffered a humeral fraction. She suffered no excessive bleeding or hematoma, and she did not require surgery. She reported a history of regular horse riding with multiple falls, without excessive bleeding. 


Her mother was diagnosed with deep vein thrombosis in the leg, which required anticoagulation. This occurred after pregnancy, which was deemed to be a contributing factor. Results of further workup or testing were unknown.


She reported no significant family history for bleeding. She has two brothers who are healthy with no medical problems. She does not smoke or consume alcohol and her only medication is prenatal vitamins.


On physical exam, she was found to be afebrile with all vital signs normal. She had no palpable adenopathy. Her right arm was noted to be in a soft cast/sling. A full skin exam revealed no rash, lesions or petechiae.


Her lab work from 1996 showed elevated aPTT of 53.8 seconds, a Factor VIII level of 42% of normal, von Willebrand’s factor (vWF) antigen 85% of normal and vWF activity 123% of normal. Repeat Factor VIII activity at that time also was low. Given that vWF acts as a carrier for Factor VIII, the Factor VIII level of 42% is lower than would be expected. This reversal in the ratio between the vWF antigen and the Factor VIII level raises the question of a possible undiagnosed hemophilia A carrier state.


Discussion


This case raises several issues when considering a hemophilia carrier with pregnancy. These include confirming a diagnosis of hemophilia, how to manage the mother and child during delivery, and how to avoid inducing 
bleeding.


In making the diagnosis of a hemophilia carrier, family history, as well as available testing, may be considered. 


Because hemophilia A and B are inherited as X-linked recessive bleeding disorders, maternal carriers would have a 50% chance of passing the disorder on to a male child. Taking this into consideration, the daughter of a hemophilic male will be an obligate carrier. Also, if a child is found to have hemophilia, the mother is a presumed carrier.


Next, a low Factor VIII to vWF antigen ratio — as seen in this case — may be an indicator of a carrier state. There is substantial error rate inherent in this method, however, due to the high variability of Factor VIII levels, including normal levels in some carriers.


The gold standard remains DNA diagnosis. The approach to genetic testing varies based on family history and disease severity. It is most informative when the specific familial mutation is known. This often is determined by testing an affected male to identify familial mutation. Testing may be done for targeted mutation analysis, sequence analysis/mutation scanning, or deletion/duplication screening.


For example, the approach to testing in a female presumed at risk to be a carrier for severe hemophilia A may include intron 22 inversion, full gene sequencing, duplication/deletion testing and intron 1 inversion. In a patient with a known family history, the approach would be to test an affected male first and then order mutation-specific testing for the at-risk female. Testing may be ordered to run simultaneously or reflexively. In pregnancy or another time-sensitive setting, typically testing is run simultaneously. Otherwise, testing may be run reflexively, with a major benefit being lower cost.


Management during delivery


This case also raises the issue of how to properly manage the mother during delivery. As mentioned, Factor VIII levels are variable in carriers of hemophilia A. The bleeding risk is seen to correlate with these factor levels, with the risk of postpartum hemorrhage increased for women with Factor VIII levels below 50%.


During pregnancy, Factor VIII and vWF increase and, therefore, the majority of women with mild von Willebrand’s disease and hemophilia A carriers do not require hemostatic support at time of delivery. Carriers of hemophilia B, however, usually will continue to have low levels of Factor IX and require additional hemostatic support.


Recommendations include that antenatal care of known or potential carriers of hemophilia be performed by obstetric units, in close consultation with a hemophilia center. In addition, it is recommended that written management plans be available, including hemostatic management of the mother and infant.


Some general recommendations found in literature include the check of Factor VIII/Factor IX levels before delivery in the third trimester. Epidural usually is considered to be safe if Factor VIII/Factor IX are greater than 40%. Use of desmopressin remains controversial during pregnancy due to concerns for potential maternal and fetal hyponatremia, as well as potential risks of placental insufficiency due to vasoconstriction and preterm labor because of oxytocic effect. However, desmopressin has been used successfully in early trimesters for bleeding prophylaxis for invasive procedures in hemophilia carriers and may be used after delivery. In addition, to reduce the risk for primary and secondary post-partum hemorrhage, it is recommended that Factor VIII and Factor IX levels be maintained greater than 50% for 5 to 7 days after delivery. 


Regarding the management of the infant during delivery, the risk for intracranial hemorrhage (ICH) in a neonate with hemophilia during vaginal delivery is small (some estimated up to 5%), but it is a serious complication. Risk of ICH in a neonate with hemophilia may be increased with cephalopelvic disproportion, precipitous delivery, a long difficult labor primarily in gravida I women, vacuum devices and forceps.


Some steps to decrease the risk for ICH include first determining fetal sex by ultrasound. If the child is male, vaginal delivery generally is considered to be safe, although a cesarean section may be considered if any of the above complications are present. In addition, management of the child should include cord blood sampling at delivery, including measurement of Factor VIII and Factor IX levels, and avoidance of scalp sampling. Intramuscular vitamin K should be avoided until the results of cord blood sampling are determined; however, subcutaneous or oral vitamin K may be used. It is recommended that procedures such as circumcision be avoided until the results of cord blood testing are determined. 


As can be seen in this case, hemophilia in pregnancy presents challenges in both the prenatal as well as antepartum care of both the mother and child. When diagnosis is unclear, testing may be performed to further determine hemophilia carrier status. This is valuable in understanding further risks and guiding management. 


References:

Chalmers E. Br J Haematol. 2011;154:208-215.

Kujovich JL. J Thromb Haemost. 2005;3:246-253.


Tim McCarthy, MD, is a fellow in hematology and oncology at the University of North Carolina at Chapel Hill. He may be reached at Physicians Office Building, 170 Manning Drive, Third floor, CB# 7305, Chapel Hill, NC 27599. Disclosure: McCarthy reports no relevant financial disclosures.


A 40-year-old woman who was 9 weeks pregnant with her first child presented for evaluation of easy bruising. 


Approximately 16 years earlier, she planned to have tonsillectomy and underwent screening coagulation studies. Those studies reportedly were normal except for a prolonged activated partial thromboplastin time (aPTT) of 53 seconds.


She then underwent further workup and reportedly was found to have a positive lupus inhibitor, although this apparently had been intermittently positive on subsequent testing.


Tim McCarthy, MD 

Tim McCarthy

Clinically, she reported a history of heavy menstrual periods when she was younger. Menses began at age 12 years and would last approximately 7 days. During this time, she experienced heavy bleeding that required change of products every hour. Her periods slowed as she aged, and they currently last approximately 4 days.


She also reported a history of easy bruising, although she denied any history of other excessive bleeding. She underwent hemorrhoid surgery 4 years prior with no significant bleeding 
complications.


In addition, 3 weeks before presentation, she fell from a horse and suffered a humeral fraction. She suffered no excessive bleeding or hematoma, and she did not require surgery. She reported a history of regular horse riding with multiple falls, without excessive bleeding. 


Her mother was diagnosed with deep vein thrombosis in the leg, which required anticoagulation. This occurred after pregnancy, which was deemed to be a contributing factor. Results of further workup or testing were unknown.


She reported no significant family history for bleeding. She has two brothers who are healthy with no medical problems. She does not smoke or consume alcohol and her only medication is prenatal vitamins.


On physical exam, she was found to be afebrile with all vital signs normal. She had no palpable adenopathy. Her right arm was noted to be in a soft cast/sling. A full skin exam revealed no rash, lesions or petechiae.


Her lab work from 1996 showed elevated aPTT of 53.8 seconds, a Factor VIII level of 42% of normal, von Willebrand’s factor (vWF) antigen 85% of normal and vWF activity 123% of normal. Repeat Factor VIII activity at that time also was low. Given that vWF acts as a carrier for Factor VIII, the Factor VIII level of 42% is lower than would be expected. This reversal in the ratio between the vWF antigen and the Factor VIII level raises the question of a possible undiagnosed hemophilia A carrier state.


Discussion


This case raises several issues when considering a hemophilia carrier with pregnancy. These include confirming a diagnosis of hemophilia, how to manage the mother and child during delivery, and how to avoid inducing 
bleeding.


In making the diagnosis of a hemophilia carrier, family history, as well as available testing, may be considered. 


Because hemophilia A and B are inherited as X-linked recessive bleeding disorders, maternal carriers would have a 50% chance of passing the disorder on to a male child. Taking this into consideration, the daughter of a hemophilic male will be an obligate carrier. Also, if a child is found to have hemophilia, the mother is a presumed carrier.


Next, a low Factor VIII to vWF antigen ratio — as seen in this case — may be an indicator of a carrier state. There is substantial error rate inherent in this method, however, due to the high variability of Factor VIII levels, including normal levels in some carriers.


The gold standard remains DNA diagnosis. The approach to genetic testing varies based on family history and disease severity. It is most informative when the specific familial mutation is known. This often is determined by testing an affected male to identify familial mutation. Testing may be done for targeted mutation analysis, sequence analysis/mutation scanning, or deletion/duplication screening.


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For example, the approach to testing in a female presumed at risk to be a carrier for severe hemophilia A may include intron 22 inversion, full gene sequencing, duplication/deletion testing and intron 1 inversion. In a patient with a known family history, the approach would be to test an affected male first and then order mutation-specific testing for the at-risk female. Testing may be ordered to run simultaneously or reflexively. In pregnancy or another time-sensitive setting, typically testing is run simultaneously. Otherwise, testing may be run reflexively, with a major benefit being lower cost.


Management during delivery


This case also raises the issue of how to properly manage the mother during delivery. As mentioned, Factor VIII levels are variable in carriers of hemophilia A. The bleeding risk is seen to correlate with these factor levels, with the risk of postpartum hemorrhage increased for women with Factor VIII levels below 50%.


During pregnancy, Factor VIII and vWF increase and, therefore, the majority of women with mild von Willebrand’s disease and hemophilia A carriers do not require hemostatic support at time of delivery. Carriers of hemophilia B, however, usually will continue to have low levels of Factor IX and require additional hemostatic support.


Recommendations include that antenatal care of known or potential carriers of hemophilia be performed by obstetric units, in close consultation with a hemophilia center. In addition, it is recommended that written management plans be available, including hemostatic management of the mother and infant.


Some general recommendations found in literature include the check of Factor VIII/Factor IX levels before delivery in the third trimester. Epidural usually is considered to be safe if Factor VIII/Factor IX are greater than 40%. Use of desmopressin remains controversial during pregnancy due to concerns for potential maternal and fetal hyponatremia, as well as potential risks of placental insufficiency due to vasoconstriction and preterm labor because of oxytocic effect. However, desmopressin has been used successfully in early trimesters for bleeding prophylaxis for invasive procedures in hemophilia carriers and may be used after delivery. In addition, to reduce the risk for primary and secondary post-partum hemorrhage, it is recommended that Factor VIII and Factor IX levels be maintained greater than 50% for 5 to 7 days after delivery. 


Regarding the management of the infant during delivery, the risk for intracranial hemorrhage (ICH) in a neonate with hemophilia during vaginal delivery is small (some estimated up to 5%), but it is a serious complication. Risk of ICH in a neonate with hemophilia may be increased with cephalopelvic disproportion, precipitous delivery, a long difficult labor primarily in gravida I women, vacuum devices and forceps.


Some steps to decrease the risk for ICH include first determining fetal sex by ultrasound. If the child is male, vaginal delivery generally is considered to be safe, although a cesarean section may be considered if any of the above complications are present. In addition, management of the child should include cord blood sampling at delivery, including measurement of Factor VIII and Factor IX levels, and avoidance of scalp sampling. Intramuscular vitamin K should be avoided until the results of cord blood sampling are determined; however, subcutaneous or oral vitamin K may be used. It is recommended that procedures such as circumcision be avoided until the results of cord blood testing are determined. 


As can be seen in this case, hemophilia in pregnancy presents challenges in both the prenatal as well as antepartum care of both the mother and child. When diagnosis is unclear, testing may be performed to further determine hemophilia carrier status. This is valuable in understanding further risks and guiding management. 


References:

Chalmers E. Br J Haematol. 2011;154:208-215.

Kujovich JL. J Thromb Haemost. 2005;3:246-253.


Tim McCarthy, MD, is a fellow in hematology and oncology at the University of North Carolina at Chapel Hill. He may be reached at Physicians Office Building, 170 Manning Drive, Third floor, CB# 7305, Chapel Hill, NC 27599. Disclosure: McCarthy reports no relevant financial disclosures.