Keywords
coagulation factors - coagulation inhibitors - factor concentrates
The lupus anticoagulant hypoprothrombinemia syndrome (LAHS) is a very uncommon disorder
and a rare exception to the widely understood premise that lupus anticoagulants (LAs)
are not associated with bleeding. LAs in general comprise a heterogenous group of
antibodies that are directed against phospholipids and thus affect the phospholipid-dependent
activated partial thromboplastin time (APTT) test in vitro, but have no true in vivo
anticoagulant effect.[1] Rarely, patients may present with laboratory evidence of a LA, along with an elevated
prothrombin time (PT) secondary to antibody specificity against factor II, leading
to a true deficiency and clinical bleeding symptoms. These constellation of findings
constitutes the LAHS.[2]
Anecdotally, we encounter approximately one to two cases of pediatric LAHS per year
in our tertiary hospital. The classic presentation is of a young child with bruising
following a recent virus. We typically take an observational approach in this setting,
with follow-up to demonstrate normalization of the coagulation profile and factor
II level along with disappearance of the LA.
We report here a highly unusual case of LAHS in a 3.5-year-old girl who presented
with more significant bleeding necessitating replacement therapy and subsequently
developed anaphylaxis to the human prothrombin complex concentrate PROTHROMBINEX-VF
(CSL Behring, Broadmeadows, Victoria, Australia). Formal consent for publication of
this case report was obtained.
The child was brought to the emergency department with a short history of bruising,
left knee swelling, and a single episode of self-limiting epistaxis. One week prior
to admission, she had confirmed adenovirus gastroenteritis. She had no significant
past medical history and no history of atopy. Examination revealed widespread bruising,
a small left knee hemarthrosis and an intensely pruritic urticarial type reaction
to adhesive dressings.
Her full blood count revealed a mildly elevated platelet count of 582 × 109/L, with
normal hemoglobin (116 g/dL) and white cell count (9.9 × 109/L) and an unremarkable
film. A basic coagulation profile (ACL TOP Analyser) demonstrated a prolonged PT of
25 seconds (normal range: 9–13 seconds) and a prolonged APTT of 66 seconds (normal
range: 24–39 seconds) which did not correct on a 50% mixing study with normal pooled
plasma.
A factor VIII assay was performed using a single-stage APTT-based system ([Table 1]) and demonstrated a normal result of 0.68 U/mL (0.5–1.5 U/mL). Factor II, VII, and
X assays were performed using a single-stage PT-based system ([Table 1]) and demonstrated a reduced factor II level of 0.09 U/mL, normal factor VII of 0.64
U/mL, and normal factor X of 0.90 U/mL (0.50–1.50 U/mL). LA testing in our laboratory
is aligned with the ISTH SSC 2009 guidelines[3] and includes dilute Russell's viper venom time and APPT (screen and confirm) pathways.
A strongly positive LA was detected.
Table 1
Methods used for coagulation assays
|
Assay
|
Method
|
|
APTT
|
ACL TOP Analyser, DG-FVIII deficient plasma; Diagnostic Grifols, Passeig Fluvial,
Barcelona, Spain
|
|
PT
|
ACL TOP Analyser, HemosIL factor deficient plasmas; Instrumentation Laboratory, Bedford,
Massachusetts, United States
|
The child was diagnosed with LAHS given the classic clinical/laboratory scenario.
The factor II inhibitor level was not performed, as this was not clinically indicated
and did not aid the diagnosis. A decision to use PROTHROMBINEX-VF was made given the
high concentration of factor II units per milliliter, theoretically requiring less
volume, perceived lower risk of adverse reactions, and negligible infectious risk
(as compared with fresh frozen plasma [FFP]). Replacement of factor II was indicated
as the child had a hemarthrosis. Following commencement of the infusion, she developed
anaphylaxis necessitating adrenaline and fluid bolus support, and made a full recovery.
A single doses of prednisone and promethazine were also subsequently administered.
Given the noncritical nature of bleeding, a decision was made to manage expectantly,
with no further plasma products transfused. Her bleeding symptoms and urticarial rash
resolved over subsequent days and upon follow-up 3 weeks later, her PT (12 seconds)
and factor II had normalized (0.97 U/mL), although the APTT remained prolonged (48
seconds) and the LA screen remained positive. At 6 months of follow-up, her coagulation
profile was entirely normal and the LA screen was negative.
LAHS was initially described by Rapaport et al in 1960.[2] Bajaj et al later described the mechanism of hypoprothrombinemia in LAHS, by demonstrating
the presence of antiprothrombin antibodies, which when bound to prothrombin are cleared
rapidly from the circulation leading to hypoprothrombinemia.[4] Adult retrospective data report an apparent predominance in younger females and
an association with autoimmune conditions, infections, and occasionally medications.[5] Bleeding is the most common presenting symptom, which is of variable severity ranging
from minor epistaxis to intracerebral hemorrhage.[5]
[6] There are no standard recommendations on management and an individualized approach
is clearly required depending on associated comorbid conditions and severity of bleeding.
Postinfectious LAHS with minor bleeding is often self-limiting,[6] particularly in children, whereas noninfectious LAHS is more likely to relapse and
require immunosuppressive therapy aimed at antibody eradication. The mainstay of immunosuppressive
therapy is corticosteroids; however, use of other agents including azathioprine, cyclophosphamide,
intravenous immunoglobulin, Rituximab, and plasma exchange are described.[5]
Previous reports describing supportive therapy for treatment of bleeding have included
the use of FFP, human prothrombin complex, vitamin K, and recombinant factor VIIa.
Given the long half-life of prothrombin (median 60 hours) and nonneutralizing nature
of the antibody, replacement of factor II (in the form of FFP or human prothrombin
complex concentrate) is theoretically feasible (in contrast to most patients with
acquired hemophilia A).
Our patient had a fairly classical initial presentation of LAHS with bleeding manifestations
following adenovirus infection. It is unusual to have to treat postinfectious LAHS
in children with factor replacement, as usually the only manifestation of bleeding
is bruising, and it is a self-limited phenomenon. The development of an antibody with
true specificity along with new atopic skin manifestations and subsequent anaphylaxis
to PROTHROMBINEX-VF in this child are suggestive of more global immune dysregulation
occurring post–viral infection, and to our knowledge this constellation of findings
has not been reported previously. The higher concentration of factor II in the concentrate
could be hypothesized to have some role in the pathophysiology of anaphylaxis in our
case. Certainly, anaphylaxis to factor IX concentrate in children with congenital
hemophilia B with inhibitors is well described, although the underlying immunological
mechanisms remain unclear.[7]
We could find only one case report of LAHS where human prothrombin complex concentrate
was used with resolution of bleeding in an adult lupus nephritis patient.[8]
We openly acknowledge that the mechanism for anaphylaxis in this scenario is not defined
and it may be simply coincidental, but given the rarity of having to treat pediatric
LAHS with factor replacement and the lack of pediatric reports of using human prothrombin
complex in this group, this unusual side effect is relevant for future treatment decisions.
Although it is unknown whether anaphylaxis would have occurred in our patient if administered
FFP, given the overall rarity of both LAHS and reported anaphylaxis to PROTHROMBINEX-VF
in other situations[9] we feel that human prothrombin complex concentrates should be used cautiously in
LAHS, particularly in the pediatric group.
