PRACTICAL PEARL

Cerebellar hemorrhage as a first presentation of acquiredHemophilia A

Dejan Micic • Eliot C. Williams • Joshua E. Medow

Published online: 14 December 2010

� Springer Science+Business Media, LLC 2010

Abstract

Background Acquired hemophilia A (AHA) is an

uncommon coagulation disorder caused by the development

of autoantibodies against coagulation factor VIII (FVIII).

While intracranial hemorrhage is a known complication of

AHA, intracranial hemorrhage as the presenting manifesta-

tion of AHA has only been described in three previous case

reports.

Method We report a case of an 86-year-old woman with

no previously reported history of coagulopathy presenting

with an acute intraparenchymal cerebellar hemorrhage and

laboratory studies demonstrating an isolated prolonged

activated partial thromboplastin time (aPTT). We discuss

an approach to the prolonged aPTT, and review the liter-

ature concerning the diagnosis and treatment of AHA.

Results Occipital decompressive craniectomy with evac-

uation of the hemorrhage was performed. Eight hours

following the procedure, the patient’s status acutely declined

with demonstration of a reoccurrence of the cerebellar

hemorrhage and new right frontal lobe hemorrhage. After

discussion with the patient’s family, life-sustaining support

measures were withdrawn. Postmortem analysis revealed a

low FVIII activity level and the presence of FVIII inhibitor.

Conclusion The presentation of intracranial hemorrhage

with an isolated prolonged aPTT is concerning for an

acquired hemophilia with FVIII deficiency. Other causes of

isolated prolonged aPTT such as a lupus anticoagulant

must also be considered. Preoperative identification and

work-up of the coagulation abnormality is essential to

guide initial treatment.

Keywords Acquired hemophilia A � Coagulation

disorder � aPTT � Intraparenchymal hemorrhage �FVIII � rFVIIa � Lupus anticoagulant

Introduction

Acquired hemophilia A (AHA) is an uncommon coagula-

tion disorder caused by the development of autoantibodies

against coagulation factor VIII (FVIII) [1–3]. Diagnosis

can be difficult as patients commonly do not have a per-

sonal or family history of bleeding [1]. Eighty percent of

the episodes involve the skin, muscles, soft tissues, and

mucus membranes, while hemarthrosis typical of congen-

ital FVIII deficiency is unusual [1, 2]. Severe bleeding

occurs in up to 90% of affected patients with mortality

rates ranging from 8 to 22%, typically within the first few

weeks following presentation [1].

The median age at diagnosis is 60–70 years; there is a

bimodal age distribution with a small peak between 20 and

30 years (mainly postpartum females) and a major peak

between 68 and 80 years [1]. Conditions associated with

the development of AHA include autoimmune diseases

(18%), pregnancy or the immediate postpartum period

(7.3%), malignancy (6.7%), drug ingestion (5.6%), and

dermatologic disorders (4.5%) [3]. In 46.1% of the cases of

AHA, no underlying disorder has been identified [3].

D. Micic

University of Wisconsin School of Medicine and

Public Health, Madison, WI, USA

E. C. Williams

Department of Internal Medicine, Section of Hematology,

University of Wisconsin School of Medicine and Public Health,

Madison, WI, USA

J. E. Medow (&)

Department of Neurosurgery, University of Wisconsin

School of Medicine and Public Health, Madison, WI, USA

e-mail: medow@neurosurgery.wisc.edu

123

Neurocrit Care (2011) 15:170–174

DOI 10.1007/s12028-010-9489-0

Intracranial hemorrhage has been reported in patients

previously diagnosed with AHA [1, 2]; however, intra-

cranial hemorrhage as the presenting manifestation of

AHA has only been described in three previous case

reports [4–6]. Here, we present the case of an 86-year-old

woman with an acute intraparenchymal cerebellar hemor-

rhage as the presenting manifestation of AHA.

Case Report

An 86-year-old woman with no previously reported history

of coagulopathy, autoimmune illness, or recent anticoagu-

lation presented to her local hospital with a severe occipital

headache, dysarthric speech, and nausea. She was confused,

with a systolic blood pressure greater than 200 mmHg.

Computed tomography (CT) scan revealed a right cerebel-

lar intraparenchymal hemorrhage measuring 3.5 cm

without midline shift (Fig. 1). She was in atrial fibrillation

and there was evidence of a urinary tract infection. She was

emergently transferred to our hospital for further care.

On presentation to our hospital she complained of a severe

occipital headache. She had movement in all extremities, and

was on a nicardipine drip with a blood pressure of 130/

54 mmHg. Laboratory investigation showed an activated

partial thromboplastin time (aPTT) of 53.4 s (reference

range 26.0–34.0 s). International normalized ratio was nor-

mal at 1.0. Liver function tests and blood cell counts were

within the normal ranges. No further coagulation studies

were done at that time.

Three hours after presentation to our hospital, the patient

underwent an occipital decompressive craniectomy with

ultrasound-guided evacuation of the right cerebellar intra-

parenchymal hemorrhage and placement of a right frontal

ventriculostomy. Bleeding was not difficult to control

during the operation and there was no evidence of hem-

orrhage in the hematoma cavity. The patient reverted to

sinus rhythm prior to surgery, and she remained intubated

following the procedure.

Immediately after surgery she was able to follow com-

mands with good strength bilaterally, and over the course

of the next 6 h she remained awake, alert, and following

commands. She remained intubated given the extent of the

posterior fossa surgery and the substantial amount of

swelling that typically accompanies this procedure. Eight

hours following surgery her status suddenly declined with

loss of all cranial nerve function and an acute drop in blood

pressure to 70 mmHg systolic. Dopamine was adminis-

tered. An emergent CT scan demonstrated a very large

posterior fossa bleed with extension into the contralateral

left cerebellum, and a secondary right frontal hemorrhage

at the site of the frontal ventriculostomy (Fig. 2). We dis-

cussed the situation with the patient’s family, including her

power of attorney, and elected not to attempt any further

surgical intervention. The patient expired soon afterward.

Postmortem laboratory testing on samples obtained just

prior to death revealed a slightly elevated thrombin time of

25.8 s (reference range 15.0–20.0 s). FVIII activity was

low at 13% (reference range 60–180%) and FVIII inhibitor

titer was 1.7 Bethesda Units.

Discussion

Only four cases (including ours) of AHA presenting as an

intracranial hemorrhage have been reported (Table 1). A

prolonged aPTT was present in all cases while further

work-up of the laboratory abnormality was delayed in three

of the four cases. Rebleeding with worsening of the clinical

condition occurred in three of the cases, ultimately leading

to death [4–6].

The presence of an isolated prolonged aPTT in a non-

anticoagulated bleeding patient is concerning for AHA, as

the aPTT is a measure of the integrity of the intrinsic and

common final pathways in the coagulation cascade (Fig. 3)

[2, 7]. Deficiency of factors VIII, IX or XI, each of which

poses a risk of bleeding, must be differentiated from con-

ditions that prolong the aPTT but do not cause bleeding.

The latter group includes deficiency of factor XII, high-

molecular-weight kininogen or prekallikrein, and the

presence of a lupus anticoagulant (LA) [7]. In one study,

the most common cause of an isolated prolonged aPTT was

the presence of LA (53.1% of cases) [8].

Fig. 1 Computed tomography (CT) scan on presentation demon-

strating a right cerebellar intraparenchymal hemorrhage measuring

3.5 cm without midline shift

Neurocrit Care (2011) 15:170–174 171

123

Inherited deficiency of a single clotting factor (e.g., VIII,

IX, and XI) can be distinguished from acquired deficiencies

due to the presence of a circulating anticoagulant by per-

forming a mixing study. Correction of the aPTT during the

mixing study indicates a clotting factor deficiency in the

intrinsic or final common pathway. If the aPTT is pro-

longed following the mixing study, an inhibitor may be

present. It is important to note that in some patients with a

FVIII inhibitor the aPTT will be normal immediately after

mixing but will be significantly prolonged after a 1 h

incubation [9].

Coagulation factor inhibitors can be divided into three

categories: anticoagulant medications such as unfraction-

ated heparin and direct thrombin inhibitors (lepirudin and

argatroban), specific inhibitors against clotting factors

(usually FVIII), and nonspecific inhibitors such as LA [7].

Administration of unfractionated heparin at therapeutic

doses typically prolongs the aPTT, whereas treatment with

low-molecular-weight heparin, even at full therapeutic

doses, rarely prolongs the aPTT to greater than 40 s [7].

Thrombin time can be useful in ruling out heparin as a

cause of a prolonged aPTT; it will be markedly prolonged

if there is enough heparin in the sample to prolong the

aPTT [7]. Differentiating between a specific inhibitor and a

nonspecific inhibitor can be determined by quantification

of the individual coagulation factors. Further quantification

of the FVIII inhibitor can be performed using a Bethesda

assay, a test that can take several hours to perform in

Fig. 2 Computed tomography

(CT) scan following acute

decompensation demonstrating

the development of a right

frontal intraparenchymal

hemorrhage measuring

5 9 3 cm and a large posterior

fossa hemorrhage measuring

6 9 3 cm

Table 1 Summary of published cases of AHA presenting with acute intracranial hemorrhage

Case Authors Presentation Laboratory studies Management Outcome

#1 Bonnaud

et al. [5]

82 year-old man with

multiple hospital

admissions including

acute subdural hematoma

aPTT: 1.56–3.45 fold

prolongation

FVIII activity: 1%

FVIII inhibitor: 4.4 BU

Multiple surgical

evacuations, prednisone,

cyclophosphamide,

rFVIIa, immunoglobulins

Discharge from hospital on

prednisone and

cyclophosphamide

#2 Marquardt

et al. [6]

68 year-old woman with

rheumatoid arthritis and

hyperthyroidism

presenting with

subcutaneous hematomas

and left sided

hemiparalysis

aPTT: 79 s

FVIII activity: 0.1 IU/mla

FVIII inhibitor: Positive

Surgical evacuation, rFVIIa

and methylprednisone 9

5 days,

cyclophosphamide,

prednisolone

Rebleed on hospital day

eight with herniation and

expiration on hospital

day 17

#3 Mashiko

et al. [4]

74 year-old man with

subdural hematoma

aPTT: 74.1–82.3 s

FVIII activity: Not reported

FVIII inhibitor: 46 BU

Multiple surgical

evacuations, FVIII and

FIX concentrates

Rebleed with thalamic

hemorrhage on hospital

day 9 and expiration on

hospital day 16

#4 Our case 86 year-old woman with

acute intraparenchymal

cerebellar hemorrhage

aPTT: 53.4 s

FVIII activity: 13%

FVIII inhibitor: 1.7BU

Surgical evacuation Rebleed 8 h following

surgery with withdrawal

of supportive care

aPTT activated partial thromboplastin time, BU Bethesda Unit, rFVIIa recombinent activated factor VII, a FVIII activity range 0.6–1.6 IU/ml

172 Neurocrit Care (2011) 15:170–174

123

specialized coagulation laboratories. One Bethesda Unit

(BU) is defined as the quantity of inhibitor that neutralizes

50% of the clotting factor activity in an equal volume of

normal plasma. The inhibitor titer has important implica-

tions for treatment, as high inhibitor titers (>5 BU/ml)

generally require the use of a bypassing agent to control

active hemorrhage.

Treatment of AHA requires two complementary strate-

gies: control of the initial bleeding episode and suppressing

production of the inhibitory antibody. In patients with high

inhibitor titers (>5 BU/ml) or in patients with life-threat-

ening acute bleeding episodes, administration of a

bypassing agent such as recombinant activated factor VII

(rFVIIa) or the activated prothrombin complex concentrate

(aPCC) FVIII inhibitor bypassing activity (FEIBA) have

been proven effective [2, 10]. Therapy with rFVIIa should

be instituted at 90–120 lg/kg intravenously every 2–3 h

while aPCC can be administered at 50–100 IU/kg intra-

venously every 8–12 h until clinical response [2]. Based on

the prior studies in congenital hemophiliacs with inhibitors,

bypassing therapy may need to continue for extended time

periods, up to 12–14 days [11]. Adverse events to use of

aPCCs have included allergic reactions and thromboem-

bolic events at high doses. The use of rFVIIa in the

treatment of bleeding episodes in AHA was complicated by

a thrombotic event in 7% of patients [12]. In patients with

low or unknown inhibitor titers, the use of FVIII concen-

trates should not delay the use of bypassing agents that are

more likely to control bleeding episodes [12]. Further

inhibitor eradication in AHA requires immunosuppressive

agents, which may be combined with extracorporeal

removal of the autoantibody. Treatment with cyclophos-

phamide and prednisone is often successful in achieving

inhibitor eradication; however, immunosuppressive ther-

apy should be tailored to the individual patient to minimize

adverse effects of the therapy such as hyperglycemia and

neutropenia [2].

Conclusion

In patients presenting with an acute intracranial hemor-

rhage and an isolated prolongation of the aPTT, a diagnosis

of AHA is suggested by the clinical picture and confirmed

by laboratory investigation [12]. History should focus on

previous bleeding episodes and previous administration of

an anticoagulant. Initial work-up should include a mixing

study and concomitant FVIII activity assay (Table 2). If

urgent surgical intervention with hematoma evacuation is

necessary prior to completion of the work-up, the patient

Fig. 3 Schematic representation of the coagulation cascade high-

lighting the factors involved in the measurement of the PTT. PTTpartial thromboplastin time, HMWK high-molecular-weight kinino-

gen, PK prekallikrein, PT prothrombin time, TF tissue factor,

TT thrombin time

Table 2 Summary of laboratory findings and treatment for causes of prolonged aPTT

Condition Laboratory findings Treatment

Inherited factor deficiency

(VIII, IX, XI)

Long aPTT corrects with mixing; low plasma

factor activity

Raise level of missing factor with specific

factor concentrate (VIII, IX) or FFP (XI)

Inherited factor deficiency

(XII, HMWK, PK)

Long aPTT corrects with mixing; low plasma

factor activity

None (deficiency does not cause bleeding)

Lupus type inhibitor

(‘‘lupus anticoagulant’’)

Long aPTT may not correct with mixing; positive

test for lupus anticoagulant; normal factor VIII

activity

None (this type of inhibitor does not cause

bleeding)

Acquired factor VIII

inhibitor

Long aPTT does not correct with mixing; low

factor VIII activity

High dose factor VIII (if low inhibitor titer)

or bypassing agent; immunosuppression

Heparin Long aPTT does not correct with mixing; markedly

prolonged thrombin time; correction with protamine

or heparinase

Neutralize heparin with protamine sulfate

aPTT activated partial thromboplastin time, HMWK high-molecular weight kininogen, PK prekallikrein, FFP fresh frozen plasma

Neurocrit Care (2011) 15:170–174 173

123

should be monitored postoperatively using serial radiologic

imaging. If progressive hemorrhage is noted, and the

diagnosis of AHA is considered based on the results of a

mixing study and FVIII assay, a bypassing agent should be

administered until clinical response [2]. Inhibitor eradica-

tion using a protocol tailored to the patient’s clinical status

should be undertaken once the acute bleeding episode has

been controlled.

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