Central Nervous System Bleeding in Hemophiliacs

Blood, Vol. 51, No. 6 (June), 1978 1 179

By M. Elaine Eyster, Frances M. Gill, Philip M. Blatt, Margaret W. Hilgartner,

James 0. Ballard, Thomas R. Kinney, and the Hemophilia Study Group

From an estimated population of 2500 sian and three had underlying congenitalhemophiliacs seen between 1965 and anomalies. No etiology was apparent in�976, 71 with documented central ncr- 38%. Sixty-five patients had intracranialvous system (CNS) bleeding were studied bleeding. Those with intracerebral bleedingretrospectively: 56 had factor VIII deficiency had a poorer prognosis than did those withand 1 5 had factor IX deficiency. More than subarachnoid or subdural bleeding. Intra-two-thirds were less than 1 8 yr old, and spinal bleeding occurred in six patients. Theone-third were age 3 yr or less when CNS combined modality rate was 34%. Of 47bleeding occurred. Thirty-eight (54%) had survivors, 12 (26%) had recurrent bleed-a history of recent trauma; one-half of ing in the absence of known trauma. Re-these had a long symptom-free interval of current bleeding 1 yr or more after the4 ± 2.2 days ( 1 SD) . Four had hyperten- initial episodes seemed to be more

From the Department of Medicine of the Pennsylvania State University College of Medicine, and

the Department of Pediatrics, University of Pennsylvania School of Medicine and the Children’s

Hospital of Philadelphia. Philadelphia. Pa.; the Department of Medicine, University of North

Carolina Medical Center at Chapel Hill, Chapel Hill, NC.; and the Department of Pediatrics. New

York Hospital-Cornell Medical Center, New York, N. Y.

Submitted November 22, 1977; accepted January 31 . 1978.

Supported by NHLBI Contracts NOl-HB-5-3016 through 3025 (cooperating centers) and NO!-

HB-5-3035 (Reference Laboratory and Coordinating Center); NIH Grant HC-06350, The Children’s

Blood Foundation of the New York Hospital; Contracts 491907 and 491908 from the Pennsylvania

Department ofHealth and Contract 223-75-OO4from the Food and Drug Administration; and USPHS

Grants MCB-420001-O1 and MCB-360001-O1.

This is a publication of the National Heart, Lung and Blood Institute Cooperative Study of Spon-

taneously Occurring Factor VIII Inhibitors in Hemophilia. The following principal investigators

comprise the Study Group: S. S. Shapiro, M.D. and i. E. Palascak, M.D., Cardeza Foundation,

Jefferson Medical College. Philadelphia. Pa. (Reference Laboratory and Coordinating Center);

F. M . Gill, M .D., Children’s Hospital of Philadelphia, University of Pennsylvania School of

Medicine, Philadelphia. Pa.; P. H . Levine, M .D., Memorial Hospital. University of Massachusetts

Medical School. Worcester, Mass.; M. E. Eyster, M.D., The Milton S. Hershey Medical Center of

the Pennsylvania State University. Hershey. Pa.; L. M. Aledort, M.D., Mount Sinai School of

Medicine, New York, N. Y.; M. W. Hilgartner, M.D., New York Hospital-Cornell Medical Center.

New York, N. Y.; W. E. Hathaway, M.D. and H. S. Hathaway, M.D., University of Colorado

Medical Center, Denver, Cob.; i. R. Edson, M.D., University of Minnesota Medical School.

Minneapolis. Minn.; C. W. McMiIlan, M.D., P. M. Blatt, M.D., and H. R. Roberts, M.D., Uni-

versity of North Carolina School of Medicine, Chapel Hill, N. C.; S. H . Goodnight, M . D., Uni-

versiI�’ of Oregon Health Sciences Center. Portland. Ore. ; C . K . Kasper, M . D., Orthopaedic

Hospital, University of Southern California. Los Angeles. Calif.; J . M . Lusher, M .D., Children’s

Hospital of Michigan, Wayne State University School of Medicine. Detroit, Mich.; i. Lazerson,

M .D., Medical College of Wisconsin and Milwaukee Children’s Hospital. Milwaukee, Wisc.; W. K.

Poole, Ph.D. and A. V. Rao, Ph.D., Research Triangle Institute. Research Triangle Park, NC.

(Statistical Methodology and Analysis Center); i. C. Fratantoni, M.D., National Heart, Lung

and Blood Institute, National Institutes of Health, Bethesda, Md. (Project Officer). Publication

Committee: J R. Edson, i. C. Fratantoni, W. E. Hathaway, W. K. Poole, S. S. Shapiro (Chair-

man).

Details of case studies including references to previously published cases will be supplied in

tabularform if requested.

A ddress for reprint requests: Elaine Eyster, M. D. , Hershey Medical Center, Hershey, Pa. I 7033.

© 1978 by Grune & Stratton, Inc. JSSN 0006-4971/78/5106-0213$02.00/0

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1 180 EYSTER El AL.

common in factor IX-deficient than in fac- cranial bleeding in hemophiliacs shouldtar VIll-deficient patients. Clotting factor include ( 1) prompt replacement therapy

concentrates to maintain minimum blood with factor VIII or IX for either cranial-levels at 30%-50% of normal were spinal axis trauma or CNS signs and symp-usually given for at least 10-14 days in toms in the absence of a history ofthose who survived. Forty-seven percent trauma, (2) documentation of bleeding by(22 of 47 survivors) had neurologic computerized tomography scanning orsequellae, such as mental retardation, other diagnostic techniques, and (3) pro-seizure disorders, or motor impairment. longed replacement therapy in patientsFrom these observations we conclude that with documented CNS bleeding.the evaluation and treatment of intra-

C ENTRAL NERVOUS SYSTEM (CNS) bleeding is the leading cause of

death among hemophiliacs.’3 Recent statistics compiled during the past

10 yr from the United States and Great Britain indicate that 25#{176}�-3O� of deaths

in hemophiliacs are caused by intracranial bleeding.2’3 Prior to 1960 the reported

mortality from CNS bleeding in hemophiliacs was � More recent figures

since cryoprecipitate and freeze-dried clotting factor concentrates have become

available suggest a mortality rate of approximately 3O%.� Associated complica-

tions, such as seizures, impaired intellectual function, or paresis, may be as high

as

During the first 2 yr ofthe Hemophilia Cooperative Study, 7 of the 1274 pa-

tients entered into the study died. Three deaths were due to intracranial

hemorrhages and one to a “stroke.” These findings prompted the more detailed

retrospective review of the courses of 71 hemophiliacs with CNS bleeding

treated since the availability of clotting factor concentrates in an attempt to

develop appropriate guidelines for the evaluation and management of this com-

plication.

MATERIALS AND METHODS

Questionnaires were sent to the principal investigators at each of the centers in the Hemophilia

Cooperative Study Group. Data were requested on (I) CNS bleeding in any hemophiliac currently

being followed or (2) any hemophiliac known to have died after 1965 with CNS bleeding. In-

vestigators were requested to estimate the number of hemophiliacs with factor VIII and factor IX

deficiency with adequate hospital records in their cachement area and areas of association.

RESU ITS

Ninety-three questionnaires were returned from investigators at twelve insti-

tutions with an estimated patient population of 2100 factor VIII-deficient and

400 factor IX-deficient patients. Fifty-six factor VIII- and 15 factor IX-de-

ficient patients had CNS bleeding documented by appropriate procedures, in-

cluding brain scans, computerized tomography (CT) scanning, arteriography,

lumbar or ventricular puncture, surgical evacuation, or autopsy. Of the 56

factor Vill-deficient patients, 27 were included in the Hemophilia Cooperative

Study.

Age andseverity (Table I). The mean age for factor VIII-deficient patients

was 14 yr with a median of 10 yr and a range of I wk to 53 yr. For factor IX-

deficient patients the mean was 16 yr. with a median of 4 yr and a range of less

than I day to 74 yr. Of 71 patients, 26 (37%) were age 3 yr or under; 38 (54%)

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CNS BLEEDING IN HEMOPHILIACS 1181

Table 1 . Ag e and Severity of Hemophilia at Onset of CNS Bleeding

Ages (yr)

Factor VIII Deficiency’

(Percent of Normal)

0- 1 2-5 6-20

Factor IX Deficiency

(Percent of Normal)

0- 1 2-5 6-20

Total

Patients

�3

4-9

10-17

�18

14 4 0

7 2 2

11 0 0

15 0 1

7 1 0

1 0 0

1 1 0

3 0 1

26

12

13

20

Total patients 47 6 3 12 2 1 71

Mean (yr)/median (yr)/range 14/10/1 wk to 53 yr 16/4/1 day to 74 yr

*lncludes four patients classified as “severe” in whom assay values were not available.

were less than 10 yr ofage; and 51 (72%) were less than 18 yr of age. Three were

newborns 1 wk of age or less.

Sixty-seven patients had severe or moderately severe disease by clinical cri-

teria, with factor assays of 5% or less. Fifty-nine of these had assays of 1% or

less. The remaining four patients had mild to moderate disease clinically, with

assays of 6%-20%.

Possible causes (Table 2). A history of significant trauma was obtained in

38 of 71 patients (54%), representing 33 instances of head injuries and 5 of

trauma to the spine. No trauma was recognized in 27 (38%), all of whom had

clinically severe or moderately severe disease. None had a record of recent

aspirin ingestion.

Hypertension, with a blood pressure of greater than 140/90 mm Hg, was

present in four patients 32, 42, 47 and 74 yr of age. None of the four had a re-

cent history of trauma. Three of the four had severe disease; one had mild

disease with a factor IX level of 20%.

Underlying congenital cerebral or cerebellar anomalies were present in three

patients. One had a large posterior fossa cyst, one had multiple dermoid cysts,

and one had an arterial-venous malformation. One ofthe three had a history of

trauma.

Presenting symptoms (Table 3). Presenting symptoms included headache

and/or vomiting in 32, seizures in 10, lethargy, irritability, or confusion in 7,

obtundation or coma in 6, and blurred vision in 1 patient with intracranial

bleeding. The 6 patients with intraspinal bleeding presented with back pain

Table 2. Possible Causes of CNS Bleeding

Factor VIII Deficiency Factor IX Deficiency

(Percent of Normal) (Percent of Normal)Total

Patients0-1 2-5 6-20-

0-1 2-5 6-20

Trauma

Head 22 3 2 6 0 0 33

Spine 2 0 1 1 1 0 5

Hypertension 3 0 0 0 0 1 4

Congenital anomaly 2 0 1 � 0 0 0 3

Noapparentcause 18 3 0 5 1 0 27

*Included in group with h cad trauma.

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Abbreviations: SDH, subdural hematoma; SAH, subarachnoid hemorrhage; IV, intraventricular hemor-

rhoge; IC, intracerebral and intracerebellar hemorrhage.

1182 EYSTER El AL.

Table 3. Presenting Symptoms

Factor VIIIDeficiency

Factor IX

Deficiency

Intracranial bleeding

Headoche and/or vomiting 28 4

Seizures 8 2

Lethargy or irritability or confusion 5 2

Obtundation or coma 5 1

Blurred vision 1 0

Unknown 7 1

Dead on arrival 0 1

Intraspinal bleeding

Paralysis 2 3

Bock pain 1 0

and/or paralysis. Presenting symptoms were not recorded in 8 patients, and I

was dead on arrival.

Symptom-free interval (Table 4). Symptoms occurred immediately after

trauma in 5 patients and within 1-12 hr in 11. In the remaining 19 with ade-

quate histories, symptoms did not occur for more than 24 hr (mean 7.8 days,

range 2-42 days). Excluding two patients with 25- and 42-day intervals, the

mean symptom-free interval following trauma was 4 ± 2.2 days (1 SD). A long

symptom-free interval was most frequent in patients with subdural hematomas

but was also seen in patients with subarachnoid or intraventricular hemorrhages

and intracerebral hematomas.

Sites ofbleeding (Table 5). Sixty-five patients had intracranial and six had

intraspinal bleeding. Twenty had bleeding into the subdural space, seventeen

into the subarachnoid or intraventricular space, and twenty-two into the cere-

brum or cerebellum. Four had bleeding in more than one site. Surgery was per-

formed in seventeen patients with subdural or subarachnoid bleeding, compared

with only three with intracerebral bleeding. Four of the six patients with bleed-

ing into the vertebral canal underwent surgery.

Recurrent CNS bleeding in patients without trauma (Table 6). Recurrent

CNS bleeding occurred in 14 of the patients, 8 of whom had factor VIII de-

ficiency and 6 of whom had factor IX deficiency; 12 of the 14 had at least one

recurrence with no known trauma. Bleeding recurred more than 1 yr after the

initial episode in eight patients, four of whom had factor IX deficiency. In five

of the eight, recurrent bleeding was documented at sites not previously de-

Table 4. Interval Between Trauma and Onset of Symptoms

in Relation to Sites of CNS Bleeding

SDH SAH or IV IC

More Than One

Site Spinal Total Patients

Immediate 2 0 2 1 0 5

1-l2hr 2 3 3 0 3 11

>24hr 11 4 2 1 1 19

Unknown 1 1 0 0 1 3

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CNS BLEEDING IN HEMOPHILIACS 1 183

Table 5. Sites of CNS Bleeding

Site Number of Patients Modality Rate

Intracranial 65 24/65*

Subduralt 20 2/20

Subarachnoidor 17 3/17

intraventricular

Intracerebral� 22 14/22

More than one site 4 3/4

Site uncertain 2 1/2

lntraspinal 6 1/6

*Includes one patient who died from complications 3 wk after CNS bleeding.

tlncludes one patient with an epidural hematoma.

t Includes two patients with intracerebellar hematomas.

scribed. Four patients had recurrent bleeding within 1 yr without known

trauma; two ofthese had Factor IX deficiency. One who was treated with fresh-

frozen plasma had recurrent bleeding in less than 1 mo; another who was

treated with factor IX concentrate had recurrent bleeding 5 mo later. Two fac-

tor VIII-deficient patients had recurrent bleeding in I and 2 mo, respectively;

one was treated with factor VIII concentrate and the other with cryoprecipitate.

Recurrent subcutaneous bleeding at the site of burr holes or sutures occurred

in three patients who had no recurrent CNS bleeding. In each instance, e-

aminocaproic acid (EACA) was begun following cessation of factor VIII; in

each instance reinstitution of factor VIII was necessary to control superficial

bleeding.

Mortality (Table 7). Twenty-four patients (34%) died as the result of CNS

bleeding. Seventeen of these died with continuous bleeding while receiving re-

placement therapy. Five of seventeen had inhibitors to the deficient factor. Two

died before appropriate therapy could be administered. In five the type and

duration of therapy was uncertain. The highest mortality rate was in patients

with intracerebral bleeding (Table 5).

One of three patients with hypertension, 5 of 23 with no history of trauma,

and 1 1 of 36 with known trauma died while receiving treatment. Three of the

latter group had sustained head trauma in snowmobile, bicycle, or automobile

Table 6. Recurrent CNS Bleeding in PatientsWithout Trauma

Factor VIII

DeficientFactor IX

Deficient

Recurrence more than 4* 4t1 yr later

Recurrence less than 2 2

1 yr later

TotaI� 6(2) 6(2)

*lncludes one patient with recurrent bleeding epi-

sodes 1 mo, 10 yr. and 10� yr later.

tlncludes one patient with recurrent bleedingthree times within 1 yr and twice several years later.

�Parentheses, number of patients with multiple

recurrences.

Table7. Mortality

Factor VIII Factor IX

Continuous bleeding

during treatment

Inhibitors 4 1

No inhibitor 9 3

Died before therapy 2 0

Type and duration 4 1

of therapy unknown

Total 19 5

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Table 9. Inhibitor Status

Factor VIII Factor IX

Deficient Deficient

1184 EYSIER El AL.

Table 8. Neurologic Sequellae in Survivors

Factor VIII Factor IX

Deficient Deficient

None 22 3

Neurologic defIcit 15 7

Seizures 7 1

Motor impairment 4* 4

Mental retardation or 5* 2

speech difficulty

Hydrocephalus 1 0

Total 37 10

*lncludes one patient with seizures.

Inhibitorpresentat 5*/4 1/1

initiation of treatment!

deaths

Amnestic response 4/0 0/0

during treatment/

deaths

Inhibitor appeared months 3/0 0/0

after successful treatment/

deaths

*Includes one patient with a previous history of a

low-titer inhibitor who died with continuous intra-

cerebral bleeding outside participating institution.

accidents. One fell from a tree, and one was hit by a baseball bat. The re-

mainder were injured in accidents such as falling while walking or playing.

Duration oftreatment. The duration of treatment in survivors with no re-

current bleeding within I yr was I 1 ± 6 days (range 5-21 days) in 1 1 patients

without a history of trauma. In 21 survivors with a definite history of trauma,

the duration oftreatment was 14 ± 10 days, with a range of 5-42 days. Factor

VIII and IX doses were variable, but minimum levels of 30%-50#{176}() were usually

maintained during therapy.

Sequellae of47 survivors (Table 8). There was no neurologic deficit in 25

survivors. However, 22 (47%) showed motor impairment, mental retardation,

or seizure disorders following bleeding episodes.

Inhibitor status (Table 9). Thirteen of 71, or l8#{176}�of the group, developed

inhibitors. Ten had inhibitors when treated, and three developed them later;

twelve were to factor VIII and one was to factor IX. Five died; one had a factor

IX inhibitor and four had inhibitors to factor VIII. In one of the four with

factor VIII inhibitors, the inhibitor status was uncertain at the time of bleeding.

Three others with high-titer inhibitors died while receiving factor VIII in con-

junction with other measures such as plasmapheresis and immunosuppressive

drugs. Four of the five survivors with inhibitors when treated had no measur-

able inhibitor present until 5-7 days after factor VIII treatment was initiated.

The remaining survivor with a factor VIII inhibitor present at the onset of CNS

bleeding was successfully treated with activated factor IX concentrate (Auto-

proplex).

DISCUSSION

The reported incidence of CNS bleeding in hemophiliacs has ranged from

2.2% to 7.8%.� These figures are in good agreement with the present survey that

suggests a prevalence rate of 2.7% for factor VIII- and 3.6% for factor IX-

deficient patients.

Others have noted that CNS bleeding occurs at all ages but is seen pre-

dominantly in young hemophiliacs.4’6 The mean age for our series of 71 pa-

tients was 14 yr. More than two-thirds of our patients were under age 18 yr.

One-third were age 3 yr or under, and three were newborns. These figures may

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CNS BLEEDING IN HEMOPHILIACS 1185

indicate an increased incidence of CNS bleeding in very young hemophiliacs

rather than reflecting the age distribution of the hemophilic population, since

ofthe 1087 patients entered in the Hemophilia Cooperative Study to date 56%

were below age 20 yr and only 1 1 .6% were below age 5 yr. Although the vast

majority had severe disease with factor levels of 0%-l% of normal, 8 patients

had factor VIII or IX levels of 2%-5%, and 4 had levels of 6%-20%. Of the

twelve patients with moderate to mild disease, 7 had a history of recent trauma

and 1 had hypertension.

Of 7 1 of our patients, 38 (53%), had a recent history of trauma, compared

to 45% of those reported by Silverstein4 and 60% of those cited in a literature

survey by Van Trotsenburg.5 Three patients had underlying congenital mal-

formations that may have been associated with bleeding. Four patients (5%)

ranging in age from 34 to 74 yr had associated hypertension, suggesting that

adult hemophiliacs with hypertension should be aggressively treated with anti-

hypertensive agents. No etiology was apparent in 38%.

The most frequent presenting symptom of intracranial bleeding was head-

ache, often with vomiting and seizures. Intraspinal hematomas usually pre-

sented with backache and/or paralysis.

A symptom-free interval of more than 24 hr with a mean of 4 ± 2.2 days was

noted in one-half of our patients with CNS trauma. A long latent period was

most frequently seen in patients with subdural hematomas but was also seen in

patients with bleeding in other sites, as reported previously.5 With the exception

of acute or chronic subdural hematomas, the vast majority of nonhemophiliacs

with posttraumatic hemorrhages have obvious signs and symptoms within the

first 24 hr. This long latent period in hemophiliacs with intracerebral hematomas

and subarachnoid hemorrhages is strikingly different and emphasizes the in-

dolent nature of bleeding following even trivial injuries.

Prior to 1974, brain scan, lumbar puncture, and arteriography were utilized

to confirm the diagnosisof CNS bleeding. More recently, the noninvasive CT

scan has become the diagnostic procedure of choice when intracranial bleeding

is suspected.7 One ofthe centers participating in the study has recently reported

the value of the CT scan in the diagnosis and management of intracranial bleed-

ing in hemophiliacs.t

As previously reported, intracranial hemorrhages were much more common

than hemorrhages within the vertebral canal.5’9 Ofour 71 patients, 65 had intra-

cranial bleeding. Those with intracerebral bleeding had the poorest prognosis,

the mortality rate being 64%. Those with subdural or subarachnoid bleeding

had a better prognosis, with a 14% mortality rate.

Indications for surgery were similar to those for nonhemophiliacs with CNS

bleeding. In our series, subdural hematomas were usually evacuated, while

subarachnoid hemorrhages and intracerebral hematomas were usually treated

medically with steroids and other agents to reduce cerebral edema. Laminectomy

was performed in the majority ofinstances for bleeding into the vertebral canal.

Of 47 survivors, 12 (26%) had recurrent CNS bleeding in the absence of

known trauma; in 4, recurrences were multiple. Replacement therapy with

plasma or plasma fractions appeared adequate in 8 patients with no history of

recurrent trauma or other predisposing cause who experienced bleeding more

than 1 yr later. Four of these eight patients had factor IX deficiency, suggesting

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1186 EYSIER El AL.

that factor IX-deficient patients may have a greater potential for recurrent

bleeding than factor Vill-deficient patients.

The high mortality rate of 34% (24 of 71) in this series emphasizes the need

for prompt, aggressive, and prolonged treatment. The necessity for prolonged

treatment with sufficient clotting factor to maintain a minimum blood level of

30%-50#{176}/� has been stressed by others.6”#{176}’2 Replacement therapy with plasma

fractions was given for an average of 10-14 days to our patients who survived

and had no recurrent bleeding. Even with such treatment, the rate of neurologic

sequellae such as mental retardation, seizure disorder, and motor impairment

was 47% (22 of 47 survivors). A high incidence of seizures associated with sig-

nificant electroencephalographic abnormalities in hemophiliacs with intracranial

hemorrhages has been previously reported.’3”4 Therefore the routine use of

anticonvulsant therapy seems justified to obviate further brain injury during

seizures.

The antifibrinolytic agent EACA was used for the treatment of CNS bleed-

ing in only 3 of our patients, although its use has been suggested elsewhere)5

However, EACA should be used with caution, if at all, in patients receiving

factor IX concentrates because of the reported association of intravascular

clotting with the use ofthis concentrate)6

There did not appear to be an increased incidence of intracranial bleeding in

patients with inhibitors. Of 71 with CNS bleeding, 13 (18%) developed in-

hibitors, compared to 207 of 1274 (16.2%) of the hemophiliacs entered into the

Hemophilia Cooperative Study. The overall mortality rate of those patients

with inhibitors at the time of treatment of CNS bleeding was 38%, a figure not

significantly different from the 34% mortality of patients without inhibitors at

the time of treatment. However, one patient with a history of a low-titer in-

hibitor and three of four patients who had high-titer inhibitors to factor VIII

at the time of presentation with CNS bleeding died, compared to none of four

who had low titer or no measurable inhibitor until they developed amnestic

responses after 5-7 days treatment with factor VIII. The one survivor who had

a high-titer factor VIII inhibitor at the time of CNS bleeding was treated with

factor IX (Autoproplex). Activated prothrombin concentrates have previously

been used for the treatment of bleeding in patients with factor VIII inhibitors.17

Based on these observations and recognizing the difficulty in deriving exact

dosage recommendations from our data, the following guidelines are suggested

for the evaluation and treatment of suspected intracranial bleeding in hemo-

philiacs:

(1) Severe hemophiliacs should receive immediate treatment for head or spinal

injury. Iftrauma is minor, but severe enough to concern the parent, patient, or

physician, a single dose of factor VIII (or IX) calculated to raise the plasma

level to at least 40#{176}/�-50%of normal is suggested. If, on the other hand, trauma

is more significant, or ifthe injury is accompanied by signs or symptoms, treat-

ment should be repeated one or more times on a 12-24-hr basis. Because of the

long symptom-free interval in many patients, the untreated patient seen within

5 days of previous significant head trauma should receive at least a single dose

of replacement therapy with factor VIII (or IX). Back injuries should always

receive prompt treatment.

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CNS BLEEDING IN HEMOPHILIACS 1 187

(2) Persistent headache, nausea, vomiting, papilledema, leg weakness, or

other neurologic signs are indications for neurologic or neurosurgical consul-

tation and diagnostic studies after treatment, even in the absence of trauma, in

any hemophiliac.

(3) Noninvasive procedures (specifically CT scanning, if available) should be

performed whenever symptoms of intracranial bleeding are present or severe

head trauma has occurred. Invasive procedures such as lumbar puncture and

arteriography are sometimes necessary.

(4) If intracranial or intraspinal bleeding is documented, a minimum level

of 30%-50% factor VIII (or IX) should be maintained for at least 10- 14 days.

(5) If bleeding is not documented by appropriate diagnostic procedures but

symptoms are present, treatment should probably be continued during an ob-

servation period of a few days.

(6) Mild hemophiliacs probably need treatment only for significant trauma

and not for trivial injuries in the absence of symptoms. Because of the unre-

liability of the history in children under the age of 8-10 yr, however, trivial

injuries should probably be treated.

(7) As in nonhemophiliacs, the use of steroids to reduce cerebral edema and

anticonvulsants to prevent further brain injury during seizures may be bene-

ficial during the acute episode.

(8) Activated prothrombin complex concentrates should be considered for

the treatment ofCNS bleeding in patients with high-titer factor VIII inhibitors.

However, experience to date has been extremely limited with this form of treat-

ment, and factor VIII concentrates remain the treatment of choice whenever

feasible (i.e., in patients with low to moderate inhibitor titers and in patients

known to have had inhibitors in the past with low titers or negative inhibitor

assays at the time ofCNS bleeding).

The above suggestions are merely guidelines. Emphasis is placed on (1) rapid

factor infusions for any known hemophiliac with suspected CNS bleeding be-

fore definitive investigation and (2) repeated transfusions for an extended

period of time after documentation of CNS bleeding. Finally, early diagnosis

in those male infants born to mothers who are obligate or suspected carriers is

essential if prompt treatment is to be instituted for intracranial bleeding in the

neonatal period.

ACKNOWLEDGMENT

We wish to thank Dr. Robert Brennan of the Division of Neurology at the Pennsylvania State

University College of Medicine for his helpful comments and suggestions.

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1978 51: 1179-1188  

ME Eyster, FM Gill, PM Blatt, MW Hilgartner, JO Ballard and TR Kinney Central nervous system bleeding in hemophiliacs 

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