Hereditary/Acquired Bleeding Disorders

Presentation and History

The patient, a pregnant 22-year-old known carrier of hemophilia A at 37 weeks gestation, first presented to the emergency department (ED) of a hospital with a low baseline factor VIII level (21%; range of normal values: 50% to 150%) and symptoms of preeclampsia. This was her first pregnancy (G1P1), and she was carrying a male child.

Her past bleeding history was significant for easy bruising; epistaxis; oral mucosal bleeding with dental extractions; and intermittent heavy menstrual bleeding. Her bleeding had been managed with intranasal DDAVP (desmopressin), Amicar (aminocaproic acid), and Lysteda (tranexamic acid). This was an unplanned pregnancy; she was followed at the hospital by specialists in obstetrics and adult hematology. The patient's factor VIII levels had been monitored during her pregnancy and ranged from 54% to 90% of normal values. Until the onset of preeclampsia, her pregnancy had progressed without complications. No genetic testing of the fetus was performed prior to delivery.

Upon presentation to the ED, the patient had vaginal bleeding with contractions, hypertension, headache, blurred vision, and edema of the lower extremities. The recommendation was to deliver the baby, so labor was induced. Before delivery, the patient received an infusion of recombinant factor VIII at a dose of 50 units/kg. Postpartum bleeding resulted in a significant drop in hemoglobin levels, which required transfusion of 2 units of packed red blood cells. Additional factor VIII concentrate was administered every 12 hours, for 2 more doses. Postpartum bleeding then normalized. The hospital was unable to perform testing for factor VIII levels.

A male child was born to the patient at 37 weeks, 3 days, via induced vaginal delivery (with no instrumentation) owing to the patient's preeclampsia. The child's birth weight was 3480 grams, and he appeared vigorous on delivery. His Apgar score was 8 (a score of 7, 8, or 9 is normal and indicates good health). There was a nuchal cord complication (nuchal cord x1) and the baby was noted to have a small cephalohematoma on the right occipital region of his head. Due to increased WOB [work of breathing], he required CPAP [continuous positive airway pressure] for 4 minutes but was weaned to room air in the delivery room. The baby's blood type was recorded as A- (DAT negative), and his mother's blood type was recorded as O+.

Evaluation and Management of the Newborn

In an outside hospital newborn and infant critical care unit (OSH NICCU), the baby underwent laboratory testing, imaging, and physical examination prior to being transferred to a specialty pediatric hospital for higher-level care and critical management.

The OSH NICCU evaluation of vital signs recorded a temperature of 97.7 degrees Fahrenheit, a heart rate of 128 beats per minute, blood pressure of 53/25, and a respiratory rate of 45 breaths per minute (98% room air; 44 is normal for newborns). Hematologic testing, in addition to confirming the baby's blood type as A- (DAT negative), showed a complete blood count (CBC) of 13.4>17.2/49.7<155 and prothrombin time/test and internal normalized ratio (PT/INR) of 16.0/1.49.

Because partial thromboplastin time (PTT) was high at 177 seconds, vitamin K was administered to the baby at birth. Since his factor VIII level was less than 1%, fresh frozen plasma and NovoEight (recombinant factor VIII; also known as turoctocog alfa) at a dosage of 50 units/kg every 8 hours were administered until his transfer to a specialty hematology center.

The baby's physical examination was normal with the exception of the small cephalohematoma on his right occipital region; however, no active bruising or bleeding was noted. Neurologic examination showed that he had normal tone throughout his NICCU stay.

A cranial ultrasound revealed echogenic contents dependent in the bilateral occipital horns with mild ventricular dilatation bilaterally; the findings are concerning for periventricular hemorrhage extending into the ventricular system, with possible early mild ventriculomegaly and grade 2/3 intraventricular hemorrhage (IVH). CT scan of the baby's head revealed layering IVH in the bilateral occipital horns, with 3 mm hyperdensity along the posterior falx and tentorium (most likely representing subdural hemorrhage), mild lateral ventricular enlargement, diffuse nonspecific cortical thinning, and biparietal scalp hematomas.

Specialty Pediatric Hospital Hematology Center Care: Evaluation, Treatment Plan, and Discussion

Upon his transfer to the hematology center at a specialty pediatric hospital, the baby underwent neurologic and hematologic evaluation.

A radiologist read the CT brain scan from the OSH and confirmed the findings of intracranial bleed. A repeat head CT was performed to assess for interval changes and showed improvement in previously diagnosed bleeds. A cranial ultrasound of the baby's brain was normal. CT of the brain performed at the specialty pediatric hospital showed interval improvement in previously seen acute intracranial hemorrhage, and the previously noted bilateral intraventricular hemorrhage was no longer apparent. A stable to decreased amount of subdural blood along the posterior falx was noted. No new hemorrhages were observed.

Hematology was consulted upon admission of the baby, and recombinant factor VIII replacement therapy with Advate at 50 units/kg every 8 hours was initiated. There was no clinical bleeding on examination. PTT was only mildly elevated at 52 seconds, and the hematocrit and platelet count were stable. The baby's factor VIII level at the specialty hospital was less than 1%.

The baby was discharged in stable condition to the care of his mother, who had also been discharged from the hospital.

The plan has been for him to continue treatment with Advate at 50 units/kg until he can be transitioned to the bispecific factor IXa- and factor X-directed antibody, emicizumab (Helimbra). The benefits and risks of treatment were reviewed with the family at the time of treatment initiation. It was communicated to them that the child would require long-term treatment to maintain higher factor VIII levels and thereby prevent the recurrence of bleeding.

Neonatal bleeding may result as a complication of labor and delivery. However, intracranial hemorrhage is an uncommon finding in the newborn with hemophilia; the incidence in full-term neonates with hemophilia is estimated at 3% to 4%.¹ The treatment for these young babies is initiation of factor prophylaxis to prevent further bleeding. This would necessitate placement of a central venous catheter for delivery of the factor infusions, a procedure that carries its own risks. With the development of new therapies such as Hemlibra (although study data in newborns are limited), the recommendation was to start Hemlibra at the 3 mg/kg loading dose subcutaneously once a week for 4 weeks, and then every 2 weeks thereafter.

The patient is now 18 months of age and there have been no new intracranial hemorrhages. He continues to be treated with Hemlibra and has not had any further hemophilia-related bleeding. His weight has been monitored closely for medication dose adjustment. He was referred to a regional center for ongoing monitoring of growth and development. While his gross motor skills are appropriate, mild speech delay has been noted. He is a happy, thriving little boy who continues to receive specialty care at a federally funded comprehensive hemostasis and thrombosis center.

In March 2021, the National Hemophilia Foundation's Medical and Scientific Advisory Council (MASAC) released guidelines for healthcare professionals to "provide recommendations for the diagnosis and management of women with bleeding disorders during pregnancy, labor and delivery, and in the postpartum period to minimize the risk of bleeding-related complications and facilitate early diagnosis of affected infants."² MASAC also provides guidelines for management in hospital EDs of intracranial hemorrhage and other serious bleeding events in people with hemophilia and other bleeding disorders.³

The body of research into gene therapy for hemophilia A and B continues to expand, with current efforts largely focused on recombinant adeno-associated viral (rAAV) vectors for F8 or F9 gene addition.⁴

References

1. Singleton TC, Keane M. Diagnostic and therapeutic challenges of intracranial hemorrhage in neonates with congenital hemophilia: A case report and review. Ochsner J. 2012;12(3):249-253.
2. MASAC document 265 – MASAC guidelines for pregnancy and perinatal management of women with inherited bleeding disorders and carriers of hemophilia A or B. March 4, 2021.
3. MASAC document 257 – Guidelines for emergency department management of individuals with hemophilia and other bleeding disorders. December 5, 2019.
4. George LA. Hemophilia gene therapy: Ushering in a new treatment paradigm? Hematology Am Soc Hematol Educ Program (2021) 2021(1):226-233.