Intracranial Hemorrhage in Persons with Hemophilia:
Risk Factors, Diagnosis, and Management

 Expert Commentary

Introduction and Overview

Intracranial hemorrhage (ICH) is one of the most serious events that can occur in patients with hemophilia (PWH). It is the leading cause of morbidity and mortality in newborns with severe hemophilia A or B, with an estimated mortality rate of approximately 20%,1-3 and this risk continues through childhood and into adult life. ICH often results in long-term neurologic and developmental sequelae, and these can significantly affect quality of life and necessitate special education for affected children. 4,5 There is an economic burden of ICH in PWH as well. In one study, the mean hospitalization stay for hemophilia newborns with ICH was 28 days versus 9 days for those with hemophilia only, with average hospital charges of $102,072 and $20,406, respectively.6 This does not take into consideration the significant degree of long-term medical and support services that are often required throughout the patient’s lifetime due to the neurologic sequelae.

Multiple studies have demonstrated that the risk of ICH is greatly increased in PWH compared with the general population.2,7,8 This is especially true in neonates, but ICH can also occur in children, adolescents, and adults with hemophilia due to a variety of risk factors. The rising use of prophylaxis over the past decade in children with severe hemophilia may, however, have contributed to the observed decrease in ICH-related mortality compared with previous years.3

This Clinical Consult is intended to provide healthcare professionals with an overview of ICH in neonates, children, and adults with hemophilia, including its prevalence, causes, risk factors, clinical diagnosis and detection, and long-term neurologic sequelae. Recommendations regarding prevention and treatment of ICH are also provided. Awareness of and implementation of evidence-based guidelines for the diagnosis and management of ICH in PWH may help reduce its occurrence and minimize its potential clinical impact for these patients.

Prevalence

The overall prevalence of ICH in the general neonatal population is thought to be low, although estimates vary. Because some cases occurring in newborns are asymptomatic and screening methods can vary, the true prevalence of symptomatic and asymptomatic ICH is uncertain. Even with use of the same screening technique (CT or MRI), variation in the reported incidence of ICH can arise from differences in study population, variation in MRI and CT sensitivity, and timing of assessment.9

Symptomatic ICH in infants without hemophilia was reported in 3.8/10,000 live births, with subarachnoid hemorrhage as the most common site.10 Others have reported that the incidence of asymptomatic, small ICH in vaginally delivered term newborns, as measured by MRI, may range from 19% to 46%.11,12 One study found subclinical ICH present in half of 8 normal, term, vaginally delivered infants, although none experienced neurologic deficits.13 These data suggest that small ICH may be a relatively common consequence of normal vaginal deliveries. In these studies, the small, asymptomatic ICH in normal newborns resolved without therapy or sequelae, but the same may not be true of newborns with severe hemophilia.

Published estimates vary, but newborns with hemophilia are thought to have a risk of symptomatic ICH that is approximately 40- to 80-fold greater than the normal neonatal population. The prevalence of symptomatic ICH in newborns with hemophilia is estimated to be between 3.5% and 4.0%, with an incidence rate of 290/105 to 748/105 patient years.8 A systematic literature review suggested that the risk of ICH in newborns with hemophilia is 44 times higher than in newborns in the general population.14 ICH is more commonly seen with severe and moderate hemophilia but can also occur in those with milder forms of the disease. The prevalence of ICH appears to be similar for hemophilia A and B.15

The prevalence of ICH in adults with hemophilia is less clearly defined. Prior to the development of effective treatments for HIV, the life expectancy for many adults with severe hemophilia did not extend beyond middle age. This has changed substantially over the past decade, and we are now seeing increasing numbers of individuals with severe hemophilia survive well beyond middle age. Risk factors for ICH in the older adult differ from those of newborns and children. As the hemophilia population ages, it is likely that we will see an increased number of those with ICH.

Age Distribution

ICH associated with hemophilia is more commonly seen in infants and in children aged 5 years or younger, although a wide age distribution is observed (Figure 1). Witmer and colleagues conducted a retrospective multicenter cohort study of the US Pediatric Health Information System (PHIS) administrative database (2002–2011) to characterize patients who experience an ICH.3 Of 3133 males younger than 21 years who were hospitalized for hemophilia A or B, 271 (3.3%) had an ICH event. The median age for ICH occurrence was 2 years (interquartile range, 0.6–7.3); 15% of ICH events occurred in patients younger than 1 month. An earlier study reported that 37% of ICH events occurred during the first week of life, 60% in the first year, and 20% between ages 1 and 3 years.16 This distribution is even more skewed in patients with severe hemophilia, where 90% of hemorrhages occur within the first 2 years of life.2

Figure 1. Age distribution of hemophilia patients with intracranial hemorrhage (1991–2001)3

Figure 1

Source: Witmer CM. Haemophilia. 2015;21:e359-e363.3 Reproduced with permission.


ICH can also affect teens/young adults and adults with hemophilia. An Argentinian survey reported that ICH occurred in 28% of hemophilia patients older than 20 years.15 Similarly, in French PWH, nearly 37% of ICH episodes were in those 15 to 50 years of age.2 One-third of these events were in patients with moderate to mild hemophilia, a trend that was more pronounced in older individuals. This suggests that age-related risk factors may predominate as patients get older and that, compared with neonates and children, older hemophilia patients have different ICH risk factors such as hypertension, thrombocytopenia, and gait or balance disturbance.1,8


Types and Distribution of Intracranial Hemorrhages

ICH can be classified neuroanatomically as epidural, subdural, subarachnoid, intraventricular, or intraparenchymal (Table 1).10 The neurologic signs of ICH can vary according to location of the bleed.

To understand the classifications of ICH, it is important to understand normal cranial anatomy (Figure 2 ).17 The dura mater is the tough outermost layer of the 3 layers of the meninges surrounding the brain and spinal cord, and it contains the venous sinuses. The arachnoid mater is a thin, middle, transparent layer connected to the pia mater by weblike filaments. The subarachnoid space, between the arachnoid mater and pia mater, is where cerebrospinal fluid (CSF) circulates. Cerebral vessels surround the surface of the brain in this area. The pia mater is the innermost delicate layer and forms a sheath around blood vessels as they course into the fissures and sulci and penetrate the brain.

Figure 2. Brain neuroanatomy17

Figure 2

Source: Morton D, et al. Gross Anatomy: The Big Picture. 2nd ed. New York, NY: McGraw-Hill Medical; 2011;chap 15.17 Reproduced with permission from McGraw-Hill Education.


A 5-year survey of 3269 PWH (all ages) reported on the distribution of hemorrhage sites in 88 cases of ICH; these included intracerebral (37.5%), subdural (34.1%), unspecified (19.3%), subarachnoid (12.5%), and epidural (8.0%).1 In comparison, in the Universal Data Collection (UDC) surveillance project the most common sites of occurrence in 633 newborns with hemophilia were subdural (68.2%), intracerebral (13.6%), cerebellar (9%), and subarachnoid and ventricular (4.6% each).18

Table 1. Neuroanatomic-based ICH in term newborns10

Type of Intracranial Hemorrhagea Definition Causes Cranial CT Scan Characteristics Pathogenesis or Comments
Epidural hematoma Blood between skull and dura Incidence highest among adolescents and young adults
Generally due to head trauma
Lentiform hyperattenuation along inner side of calvarium Rare
Middle meningeal artery moves freely away from displacements of the skull
Result of bleeding from artery or venous sinus that tears, often with skull fracture
Subdural hematoma Blood between dura mater and arachnoid mater Generally due to head trauma Crescent-shaped hyperattenuation conforming to the adjacent brain More common
Vertical molding of skull causing tearing of blood vessels of tentorium
Typically caused by tear of bridging veins from surface of brain to dural sinuses; or from arterial rupture
Subarachnoid hemorrhage Blood between arachnoid and pia mater Often caused by rupture of congenital saccular “berry” aneurysms
Can also arise from trauma, intracranial arterial dissections, vacuities, arteriovenous malformations or fistulae
Hyperattenuating fluid in basal subarachnoid spaces or along cerebral sulci More common
Tearing of bridging blood vessels or dural sinuses during labor
Intracerebral and intraventricular hemorrhageb Blood in lateral, third, or fourth ventricles Caused by rupture of blood vessel in brain and resulting blood flow into adjacent brain tissue
Intraventricular hemorrhage characterized by blood within CSF-filled ventricles
Hyperattenuating fluid typically seen as layering within ventricles Uncommon
Hemorrhage of choroid plexuses, extension of thalamic or subependymal matrix
Intraparenchymal hemorrhage Blood within brain (intra-axial) parenchyma Hyperattenuating focus within the cerebral or cerebellar hemispheres, with varying amount of surrounding vasogenic edema Less frequent
Primary hemorrhage must be distinguished from secondary intraparenchymal hemorrhage

aLocation of intracranial hemorrhage may be supratentorial or infratentorial (most common).
bUnlike term newborns, 80% of preterm infants with intraventricular hemorrhage are associated with germinal matrix hemorrhagic infarction. Occurrence of intraventricular hemorrhage in term newborns is a poor predictor of neurologic outcome.

Source: Gupta SN, et al. Pediatr Neurol. 2009;40:1-12.10 Adapted with permission.


What are some of the risk factors for ICH in patients with hemophilia?                         

Heisel-Kurth

Risk Factors and Clinical Presentation

Newborns and children up to 2 years of age.
For newborns and young pediatric hemophilia patients, the greatest risk factors for ICH are associated with birth-related factors and trauma. In newborns, trauma from delivery is a significant risk factor for those with or without hemophilia, and it is related to use of forceps, vacuum extraction, fetal scalp monitors, and prematurity.19,20 An analysis of 583,340 singleton infants born to nulliparous women assessed the prevalence of symptomatic ICH in the general neonatal population and the effects of mode of delivery.21 ICH occurred in 1 of 860 infants delivered by vacuum extraction, 1 of 664 delivered with forceps, 1 of 907 delivered by C-section during labor, 1 of 2750 delivered by C-section with no labor, and 1 of 1900 delivered spontaneously. Compared with spontaneous delivery, vacuum extraction was associated with a significantly higher rate of subdural or cerebral hemorrhage (odds ratio [OR] 2.7; 95% CI, 1.9-3.9), as was use of forceps (OR, 3.4; 95% CI, 1.9-5.9) and cesarean delivery during labor (OR, 2.5; 95% CI, 1.8-3.4). The increased risk of ICH in all infants with birth trauma is further increased in newborns with hemophilia. In a review of the literature, James and Hoots state that risk of ICH in infants with hemophilia is elevated with forceps delivery and argue for elective cesarean birth in pregnancies in which the mother is known to be a carrier and where there are other risk factors.19

Clinical Presentation

ICH can be the presenting symptom of a severe coagulation deficiency such as hemophilia in cases where there is no family history of congenital bleeding disorder. Up to one-third of hemophilia newborns do not have family history of the disease, so healthcare providers may not always consider the potential effects of mode of delivery in advance; therefore, a diagnosis of ICH may not be immediately suspected.

Symptomatic ICH in newborn hemophilia patients typically presents within the first week of life, with a mean age of diagnosis of 4.5 days (range, birth–28 days).22,32 As noted earlier, both symptomatic and asymptomatic ICH can occur in neonates. Initial clinical presentation of symptomatic ICH may be nonspecific, with symptoms common to other conditions such as meningitis and sepsis. Kulkarni and Lusher reviewed 109 published cases of symptomatic cranial bleeds in infants with hemophilia.23 Lethargy, anemia, hypotension, and shock were common in both intracranial and extracranial bleeds, while seizures, bulging fontanelle, and neurologic sequelae occurred more frequently in those with ICH. Other studies have found that in children younger than 2 years, common initial symptoms of ICH are unusual crying, apathy, vomiting, and coma (Figure 3).2,24 During the course of the ICH, coma occurred in two-thirds of all cases, regardless of age.

Figure 3. Possible clinical signs of ICH in neonates24

Figure 3

Hypotension, tense fontanelle, pupillary/ocular changes, and apnea.
* Frequent first documented symptoms among children aged <2 years.

Source: Singleton TC, Keane M. Ochsner J. Fall 2012;12:249-253.24 Reprinted with permission.


ICH is a common site of initial bleeding in infants with hemophilia. The US Hemophilia Treatment Center network evaluated 864 male infants (0–2 years of age) with hemophilia who were enrolled in the UDC surveillance project.18 Cranial hemorrhages were the second most common site of initial bleeding episodes (17.7%), and ICH accounted for one-third of such cases (Figure 4). Other locations included circumcision (45.5%), iatrogenic heel-stick bleeding (14.8%), venipuncture (3.6%), and miscellaneous sites including soft tissue, oral mucosa, and other (≈12% total).

Figure 4. Leading sites of initial bleeding episodes in newborns with hemophilia18

Figure 4

Source: Kenet G, et al. Haemophilia. 2010;16(Suppl 5):168-175. Adapted with permission.


ICH accounted for 33% of cranial hemorrhages in this study.

Children and Adolescents
In children (2 years and older) and adolescents, ICH occurs in 3% to 10% of the hemophilia population.8 Risk factors for this group include trauma, severe hemophilia, presence of inhibitors, and history of a prior ICH. In an evaluation of 26 cases of ICH in this population, clinical signs and symptoms were headache (67%), coma (66%), vomiting (46%), motor dysfunction (37%), neurovegetative dysfunction (26%), seizure (21%), and aphasia (20%).2 Focal neurologic deficits, mental status changes, and visual disturbance can also occur. Symptoms increase gradually over time (minutes to hours) as the hematoma progresses.25 Neurologic outcomes tend to be better in this age group compared with neonates. One author has suggested that this may be due to the greater vulnerability of the newborn brain.16 It should be emphasized, however, that approximately one-half of all ICH episodes in pediatric hemophilia patients detected by entry MRI are clinically asymptomatic.

In older children, trauma associated with sports participation may be a risk factor. A case-control study analyzed 10,262 PWH 2 years of age or older who were enrolled in the CDC UDC project.26 Using multivariate logistic regression analysis, risk of ICH was significantly increased by the presence of inhibitors (OR 4.01), previous ICH (OR 3.62), and severe hemophilia (OR 3.25). HIV infection was associated with elevated risk of ICH but was not statistically significant in this study. Notably, the use of prophylaxis in patients with severe hemophilia was associated with a significant reduction in risk of ICH in those without HIV infection and in patients who did not have inhibitors (≈50% reduction for both). Other studies have confirmed that ICH is more common in hemophilia patients receiving on-demand therapy compared with prophylaxis.1,7

Adults
Adults with hemophilia are also susceptible to ICH. Older literature suggests that in contrast with children, most cases in patients older than 50 years are nontraumatic in origin and are more likely due to other risk factors such as hypertension and presence of inhibitors.27 However, since the introduction of effective treatments for HIV and HCV, many adults with hemophilia are now surviving to older age. These individuals typically have hemophilic arthropathy in multiple joints that may impair gait and balance and thus increase risk for falls with subsequent head trauma. In one center’s experience, 4 of 5 cases of ICH over the past several years have been directly related to traumatic head injury from falls [M. Reding, personal communication]. Nearly half of ICH episodes occur in those with mild or moderate hemophilia. Common symptoms of ICH in adults are persistent headache and altered mental status (including coma), and a diagnosis of ICH should be considered in those with head trauma or history of hypertension.


Neurologic Sequelae of ICH

ICH occurring in newborns can result in varying degrees of neurologic sequelae, ranging from no apparent neurologic effects to significant impairment or death. It is estimated that 40% to 60% of infants with hemophilia and ICH will subsequently exhibit neurologic sequelae, including seizures.28

The effects of ICH in older children can similarly vary and can include decreased motor function, visual-motor integration problems, lower intellectual functioning, and reduced language-related skills.4,29

What are some of the considerations in screening a newborn with severe or moderate hemophilia for possible ICH?                         

Sidonio

Methods for Detection of ICH

Optimal management of ICH in PWH depends on an immediate diagnosis of the hemorrhage and prompt institution of factor therapy to ensure hemostasis. Early, accurate detection is therefore critical since neurologic deterioration tends to occur within the first few hours following onset of ICH. Prompt therapeutic factor administration should lower the probability of extension of the bleeding, and thus limit neurologic sequelae and improve outcomes.26

Three imaging methods are used for detection of ICH: cranial ultrasound (only used in infants younger than 9-12 months), CT scans, and MRI (Table 2). Currently, consensus and guidelines are lacking on recommended imaging method(s) for detection of ICH in symptomatic newborns.

In newborns, cranial ultrasound is often considered initially as a method to diagnose an ICH. Advantages of this imaging method include low cost, lack of radiation exposure, and no requirement for sedation. Cranial ultrasound does not always detect ICH, especially those bleeds that are relatively small or where bleeding occurs in the posterior fossa.30 Moreover, a negative ultrasound does not absolutely rule out an ICH, so a more sensitive confirmatory scan (noncontrast CT or MRI) is required. Cranial ultrasound may not be available outside hospitals, and it requires the operator to have experience with neonatal ultrasound. Bleeds detected on ultrasound also require additional CT or MRI to further define the bleeding. For all these reasons, cranial ultrasound is not considered the optimal method of diagnosing an ICH in a symptomatic newborn with hemophilia.

Table 2. Methods for detecting intracranial hemorrhage


Advantages Disadvantages Comments
Cranial ultrasound
  • Easy to perform
  • Inexpensive
  • Avoids radiation exposure to infant
  • May only be used in newborns and infants with an open fontanelle
  • Low sensitivity
  • Limited ability to detect subdural and subarachnoid hemorrhages
  • Follow-up scans using more sensitive methods may be required for confirmation and/or characterization
  • May be more likely to detect abnormalities accompanied by macrocephaly, seizures, or 1-minute and 5-minute Apgar scores of <7
  • Operator must have experience with neonatal ultrasound
CT scan (noncontrast)
  • Widely available
  • Higher sensitivity than ultrasound for ICH in infants
  • Performed rapidly (2-4 min scan time)
  • Rarely requires sedation
  • Typically method of choice in adults
  • Radiation exposure to neonates/young children
  • Higher cost than ultrasound
  • Some investigators recommend use of CT (or MRI) scan in infants with symptoms suggestive of ICH, even with apparently normal ultrasound findings
MRI scan
  • Higher sensitivity than ultrasound for ICH in infants
  • No radiation exposure
  • Usually does not require sedation for older children and adults
  • May require anesthesia in infants (scan time 40 min)
  • Costlier than ultrasound or CT scans
  • Small bleeds can be missed at birth
  • Gradient echo sequence MRI or susceptibility-weighted imaging may be superior to standard MRI due to enhanced sensitivity, but not always available


CT scans are widely available and can be performed rapidly. Importantly for neonates, they do not require sedation and are sensitive at detecting small amounts of intracranial bleeding. Disadvantages of CT scans include a limited amount of radiation exposure (primarily to the head and neck) and higher cost compared with ultrasound. In neonates with symptoms suggestive of ICH, CT or MRI should be considered, even with an apparently normal cranial ultrasound.31 Noncontrast CT scans are typically the detection method of choice in older children and adults with suspected ICH (Figure 5).

ICH can also be diagnosed by means of MRI, which can be performed without the need for contrast or risk of radiation exposure. Sedation is not needed in most older children and adult patients, although this may be required in neonates and young children. Compared with CT, MRI incurs a higher cost and involves a longer scan time (about 40 minutes). T1-weighted magnetic resonance imaging can miss small amounts of blood during the initial 1 to 3 days following ICH onset, however. Due to its greater sensitivity for detecting bleeding, gradient echo sequence MRI or susceptibility-weighted imaging may be preferred over standard MRI, but these techniques are not available in many non-tertiary hospitals and may require contrast administration.10 Whitby et al used a small, low-field-strength (0.17 T) MRI scanner for detection of ICH in neonates, without the need for sedation.32 This method was shown to be more sensitive than ultrasound, especially in the posterior fossa and peripheral regions of the brain.

In summary, for symptomatic newborns a noncontrast CT scan or MRI should be used to diagnose an ICH. For older children and adults, a noncontrast CT scan is more frequently used for diagnosis, but an MRI may also be used.

Guidelines are lacking on whether and how asymptomatic neonates with a diagnosis of hemophilia should be screened for ICH. Some providers oppose routine scanning, while others suggest it can have a role in high-risk situations such as delivery with use of forceps or vacuum extraction, or for prolonged second stage of labor. Other providers suggest that all newborns with severe and moderate hemophilia should undergo routine screening. Screening using cranial ultrasound is not recommended in an asymptomatic newborn with hemophilia, as explained in the section above. Some providers have suggested that rather than screening, short-term prophylaxis should be considered in high-risk situations, but this approach has the distinct disadvantage of increased risk of inhibitor development, particularly with recombinant factor VIII.33

Other providers are proponents of broader screening, citing the significant incidence of small ICH in all newborns. The theory is that these small bleeds in newborns with hemophilia may lead to the symptomatic bleeds that are diagnosed usually several days following birth. This may then prevent the more devastating ICH in these newborns and perhaps decrease neurologic sequelae. Those who favor noncontrast CT cite its accuracy in detection of smaller lesions, easy availability of CT scans, and the lack of need for sedation. Other providers consider MRI as the optimal method of screening because of the lack of radiation exposure. However, if anesthesia is needed for MRI, this may delay the scan, thus outweighing the potential benefits of this method. Finally, aggressive screening of all neonates with moderate to severe hemophilia may not be cost-effective.34,35

Figure 5. CT scan of newborn with ICH


Figure 5

[Image courtesy of Dr. T. Singleton]

What are the current recommendations regarding delivery for a woman who is a known carrier of hemophilia?                         

Reding

Prevention

Newborns

Recommendations for perinatal management of women with bleeding disorders or carriers of hemophilia A and B have been issued by the National Hemophilia Foundation’s Medical and Scientific Advisory Council (MASAC) (Table 3).36 The delivery team should be informed of a prenatal diagnosis of hemophilia or carrier status of the mother prior to the delivery.

There is currently a lack of consensus on the optimal delivery method of infants with hemophilia (vaginal vs cesarean) in order to minimize risk of ICH during birth.20,37,38 In the United States, cesarean delivery is more commonly used for hemophilia carriers.22 A systematic literature review and meta-analysis identified 4 prospective studies evaluating the effect of mode of delivery on risk of ICH in newborns with hemophilia. Compared with unassisted vaginal delivery, the odds ratio for developing ICH was 4.4 (95% CI, 1.46–13.7; P = 0.008) following assisted vaginal delivery and 0.34 (95% CI, 0.14–0.83; P = 0.018) following cesarean birth.14 Therefore, it is critical to avoid use of vacuum extraction, instrumental delivery, and fetal scalp monitors that can significantly increase risk of ICH during delivery.

For pregnant women who are at high risk for ICH in their newborns, a multidisciplinary team with expertise in bleeding disorders should manage pregnancy and delivery. This could include an obstetrician, coagulation disorders specialist or pediatric hematologist, pediatric neurologist, neonatologist, neuroradiologist, pediatric neurosurgeon, and social worker.10 A genetic counselor may also be involved for consultation in cases of previously undiagnosed hemophilia. Upon discharge, patients and their pediatricians or general practitioners should be informed of any new diagnosis of hemophilia and the risk of developing ICH, including high-risk activities as well as early signs and symptoms, to ensure prompt diagnosis and treatment.

Table 3. MASAC guidelines for perinatal management of women with bleeding disorders who are carriers of hemophilia A or B36

  • Recommend preconception screening and genetic counseling for women who are at risk for being carriers of inherited bleeding disorder
  • Ensure patient management by multidisciplinary team including coagulation disorders specialist, obstetrician, and anesthesiologist who have experience with bleeding disorders
  • Delivery should occur in a facility equipped to handle bleeding complications during delivery and postnatally and one that has necessary lab, pharmacy, and blood bank support
  • Develop a management plan for childbirth
  • Administer factor replacement prophylactically at delivery if maternal factor levels are low (<50%)
  • Discuss delivery options with the mother in advance, including the fetal and maternal risk with a vaginal delivery versus a planned cesarean birth
  • In those women who elect vaginal delivery, forceps and vacuum extraction (interventions that triple the risk of intracranial hemorrhage in affected infants) should be avoided, as should fetal scalp electrodes during labor
  • Take appropriate precautions to prevent postpartum hemorrhage and minimize blood loss. Factor levels should be monitored, as they may drop following delivery
  • If factor concentrate replacement therapy is necessary, prophylaxis should be continued for 3–5 days postpartum

MASAC, Medical and Scientific Advisory Council.


Are there additional preventative measures that can be used in older children and adults with hemophilia to help prevent ICH?                        

Kurth

Older children and adults

Prevention of ICH in adolescent and adult PWH is less well studied. Many adolescents now use prophylaxis, which will likely decrease the incidence of ICH with trauma, but a study to confirm this has not been undertaken. In adolescents, it is well known that adherence to prophylaxis is often not optimal, and this will negate some of the possible benefits of prophylaxis in preventing ICH. Older children and adolescents often engage in high-risk behaviors, and they are less likely to report an injury or respond to it promptly with factor concentrate administration. As patients transition to adult care during these years, it is important for healthcare providers to address these issues in terms of patients’ goals (eg, being with friends, going to college). Because these adolescents spend more time with peers and less with their parents, their friends should know that the patient has hemophilia and what to do in case of an accident.

In adults, efforts to maintain long-term adherence to factor prophylaxis is an important step toward reducing the risk of traumatic bleeds including ICH. Monitoring for and aggressively treating cardiovascular disease risk factors may also reduce the risk of hemorrhagic stroke, which is of particular relevance in the aging hemophilia population. Education to increase awareness of the impact of hemophilic arthropathy on gait stability and balance, and regular physical therapy evaluation and treatment (including the use of assistive devices, orthotics, etc), can also help reduce the risk of falls that could result in ICH.

What is the recommended treatment for an ICH in newborns?                                                   

Guelcher

Treatment

Medical interventions for ICH, including administration of factor concentrate and diagnostic testing, should be implemented immediately upon initial clinical suspicion of such a diagnosis, with a goal of attaining 100% factor levels. This may include patients (newborn, children, and adults) who are symptomatic or older children and adults who are asymptomatic but have had recent significant head trauma. In cases where ICH is confirmed, the therapeutic factor concentrate (FVIII or FIX) should be continued to control bleeding and prevent extension of ICH.34,39 PWH who also have an inhibitor and develop an ICH can be a challenge to treat and require bypassing agents unless they have a low-titer inhibitor, which can be overwhelmed with standard factor concentrate.

In newborns who are not symptomatic, providers utilizing screening scans generally await results before instituting factor concentrate, but if the delivery involved instrumentations or was particularly traumatic, then factor concentrate should be administered prior to the scan.

No consensus exists on the optimal duration and type of factor that should be administered immediately following a diagnosis of ICH in newborns. In cases where hemophilia has not been previously diagnosed (eg, no family history), initial treatment often involves fresh-frozen plasma (FFP), and appropriate factor concentrate (FVIII or FIX) should be administered immediately following confirmation of the disorder as either hemophilia A or B. This has been shown to be effective in controlling ICH in patients with hemophilia A or B.40,41 In general, most clinicians treat until there has been resolution of the intracranial bleed, which may require 4 to 8 weeks. Aggressive prophylaxis is then started and continued indefinitely.

Recent results from the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) study may have implications for the type of factor used in newborns and other minimally treated or untreated patients with hemophilia A. In this trial, the risk of developing inhibitors within the first 50 exposure days was approximately 1.7-fold higher with recombinant factor VIII concentrate than with von Willebrand factor (VWF)-containing plasma-derived (pd) factor VIII concentrates.33 Because the study only evaluated intermediate-purity pdFVIII products that contained VWF as the comparator and not all pdFVIII products or extended half-life factors, the clinical significance of these results is unclear but could impact the type of replacement factor chosen in newborns with hemophilia diagnosed with ICH.

What is the recommended treatment for an ICH in older children and adults?                         

Guelcher

Case Studies

Case 1
Baby boy CM was born at 40 weeks’ gestation to a G1 P0000 female. There was no family history of bleeding disorders or significant bleeding symptoms. Pregnancy was uncomplicated, and there was no use of forceps or vacuum extraction. There was no evidence of scalp molding, and the remainder of the exam was normal. Because the baby had prolonged bleeding from a heel poke, screening coagulation studies were obtained that showed a markedly prolonged PTT and FVIII level of <1%. An ultrasound was normal, but the hematologist recommended that a CT scan without contrast also be obtained, which showed a small/moderate bleed in the posterior fossa. The patient was treated with replacement FVIII concentrate. At 3 to 4 weeks the bleed had resolved, and the patient was continued on factor prophylaxis.

It is estimated that at least 30% of newly diagnosed hemophilia patients have no family history of the disorder. The most common presentation of hemophilia in the newborn period usually relates to a bleeding circumcision, bleeding from a heel poke, or cephalohematoma/subgaleal bleeding. It is also possible that a symptomatic CNS bleed may be the initial symptom of an underlying bleeding disorder, but in hemophilia patients these bleeds usually become evident on average at day 4 to 5 of life and after the baby has been discharged. This baby was diagnosed with hemophilia one day after birth, following prolonged bleeding from a heel poke. At that time, the neonatologist who was consulted ordered a head ultrasound to assess for a CNS hemorrhage. Head ultrasounds are generally ordered in the NICU for assessment of ventricular bleeding but are known to miss posterior bleeding. In this case, the neonatologist was comfortable discharging the baby with a normal cranial ultrasound. The hematologist strongly suggested the noncontrast CT, which showed a significant CNS bleed. If the patient had been discharged, he most likely would have become symptomatic in the following days, at which time the bleed would have been considerably larger, and the baby would then have been at risk for more serious neurologic sequelae. The question, of course, is whether a noncontrast CT or MRI scan should have been performed. Both have their advantages and disadvantages, but the CT scan is easily available and does not require sedation.

Case 2
AA is a 14-year-old boy who has a diagnosis of severe hemophilia A. He had done well over his early childhood, without any major bleeding issues. He had been on prophylaxis since 15 months of age and had no significant chronic joint issues. In adolescent years, his prophylaxis adherence had not been optimal. While on vacation with his family he went body surfing, which “got a little rough.” He did not recall a head injury, but 72 hours following the body surfing he began to experience headaches and nausea that persisted and worsened. In retrospect, his sister recalled one large wave that had pounded her brother into the sand. He was treated with his usual prophylaxis dose when the symptoms developed, but when symptoms worsened, the family called the hemophilia treatment center. He was told to treat with 50 units/kg of factor VIII and sent immediately to an emergency room, where a CT scan showed a mild/moderate subdural collection of blood over the left temporal lobe. He was continued on factor VIII concentrate for 4 weeks until there was substantial improvement in the bleed. He was then continued on a more aggressive prophylaxis schedule. The subdural bleed was monitored until complete resolution.

Adherence to prophylaxis can become difficult in the adolescent PWH. Unfortunately, this coincides with a time in life when these patients are also more likely to participate risky activities and sports. If this patient had been adherent to his prophylaxis schedule, this might have prevented the bleeding episode. Also, a dose given immediately following the activity could have influenced the outcome of the ICH. Clearly, it is important to stress adherence to prophylaxis and work with the patient and family to overcome barriers to adherence. There should be an ongoing discussion about sports participation, as well as education about signs and symptoms of an ICH. Providers should also stress the need to rapidly access medical care if these symptoms develop and to administer a dose of factor concentrate that will raise the factor level to 100%.

Case 3
BB is a 75-year-old male with severe hemophilia A, with advanced hemophilic arthropathy in multiple joints. Comorbid conditions include long-standing HIV infection (well controlled), chronic HCV (untreated), hypertension, and chronic renal failure (dialysis-dependent for 12 years). He receives factor VIII prophylaxis 3 times per week prior to accessing his AV fistula for dialysis. On this regimen, he has had only rare breakthrough bleeds over the past several years. While ambulating in his home, he tripped and fell, striking his forehead on the floor. This resulted in a large forehead hematoma (extracranial) and small bilateral subdural hematomas (Figure 6A). He was hospitalized and treated with factor VIII to maintain normal levels and did not require neurosurgical intervention. After several days, he was discharged home on daily factor VIII replacement therapy, which he continued for 4 weeks. At that time repeat imaging showed that the hematomas were resolving as expected, and he returned to his regular factor prophylaxis schedule.

One month later, he developed sudden onset of headache, altered mental status, and slurred speech. CT scan revealed an acute-on-chronic subdural hematoma, which was markedly increased in size compared with the previous scan, and associated with mild subfalcine herniation and midline shift (Figure 6B). There had been no falls or other trauma, but his blood pressure had been more elevated and labile over the previous month. Despite aggressive treatment including factor VIII replacement to normal levels, neurosurgical evacuation of the hematoma, and aggressive blood pressure control, he ultimately died of complications related to this event.

This case illustrates the ongoing risk of ICH related to falls in older PWH, which is exacerbated by gait and balance alterations secondary to hemophilic arthropathy, as well as the potential contribution of other risk factors such as vascular disease and hypertension.

Figure 6. Elderly patient with intracranial hemorrhage following head trauma (Case 3)

A. Figure 6A
B. Figure 6B

[Image courtesy of Dr. M. Reding]


CT scans of an elderly man who sustained head trauma due to a fall, resulting in a large forehead hematoma (extracranial) and small bilateral subdural hematomas (circles; Figure 6A). Despite daily factor VIII replacement for 1 month, followed by return to regular prophylaxis 3x/week, 2 months following the initial event he developed an acute-on-chronic subdural hematoma associated with mild subfalcine herniation and midline shift (arrowheads; Figure 6B).