Seminars in Arthritis and Rheumatism ] (2014) ]]]–]]]

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Seminars in Arthritis and Rheumatism

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n CorrE-m

journal homepage: www.elsevier.com/locate/semarthrit

De novo neonatal antiphospholipid syndrome: A case report andreview of the literature

Oren Gordon, MD, PhDa,n, Yotam Almagor, MDa, Dvora Fridler, MDa, Asaf Mandel, MDb,Hiba Qutteineh, MDa, Asaf Yanir, MDc, Shimon Reif, MDa, Shoshana Revel Vilk, MD, MScc

a Department of Pediatric, Hadassah Hebrew-University Hospital, Ein-Kerem Campus, Jerusalem 91120, Israelb Pediatric Intensive Care Unit, Hadassah Hebrew-University Hospital, Jerusalem, Israelc Department of Pediatric Hematology/Oncology, Hadassah Hebrew-University Hospital, Jerusalem, Israel

a r t i c l e i n f o

Keywords:Neonatal thrombosisAntiphospholipid syndrome

x.doi.org/10.1016/j.semarthrit.2014.04.00372/& 2014 Elsevier Inc. All rights reserved.

esponding author. Tel.: þ972 26 776 465; faxail address: orengo@hadassah.org.il (O. Gordo

a b s t r a c t

Objectives: Neonatal antiphospholipid syndrome (APS) is rare and only few cases have been reported,most of them describing trans-placental passage of penetrable maternal antibodies. The current articleaims at defining the clinical and biochemical features of the de novo occurrence of neonatal APS andconsiderations for long-term treatment.Methods: We present a case and review the medical literature using PubMed.Results: Including the current report, there are 11 reports of de novo neonatal APS. These include 8 casesof acute ischemic stroke, 2 of venous thrombosis, and 1 of mixed arterial and venous thrombosis. Allcases had an additional thrombotic risk factor, either inherited or acquired. Negative maternal historytogether with low clinical suspicion led to late diagnosis in most cases. In all cases aPL antibodiespersisted in the serum throughout the follow-up period. No recurrence of thrombotic events wasreported in patients under long-term anticoagulation with either low-molecular-weight heparin(LMWH) or aspirin. There is 1 report of recurrent thrombosis where the patient did not receiveanticoagulation. In this case diagnosis was made only retrospectively after recurrence.Conclusions: We recommend that de novo APS be considered in all cases of unexplained neonatalthrombosis aiming at early diagnosis and implementation of long-term anticoagulation to preventrecurrent thrombotic events.

& 2014 Elsevier Inc. All rights reserved.

Introduction

Thromboembolic events are uncommon in children. Within thepediatric population, however, neonates bear greater risk forthrombosis and its sequela [1–4]. This may be explained by thecoalescence of unique perinatal and maternal risk factors togetherwith acquired or inherited thrombophilic risk factors [2–5].Determining risk for recurrence is essential for the long-termmanagement of neonatal thrombosis [6].

Antiphospholipid syndrome (APS) is a non-inflammatory auto-immune disorder characterized by the association of thromboticevents in combination with persistent elevated titers of antiphos-pholipid (aPL) antibodies, such as lupus anticoagulant (LAC),anticardiolipin antibodies (aCL), or anti-β2 glycoprotein-I anti-bodies (aβ2GP1), as defined in the Sapporo criteria [7–9]. APSmay be primary or secondary to other autoimmune diseases,

: þ972 26 778 921.n).

mainly systemic lupus erythematosus (SLE). Pediatric APS is rarebut holds a risk of death or severe morbidity [7,10]. Thus far, only afew cases of neonatal APS have been reported, most of themdescribing neonatal APS arising from trans-placental passage ofpenetrable maternal antibodies [11–15]. While it is reasonable toassume that neonatal APS related to trans-placental passage of aPLantibodies differs in clinical course and prognosis from de novoproduction of aPL antibodies by the neonate itself, little is knownabout the later.

Case report

A 9-day-old male infant presented with a hard, swollen, purpleleft leg. He is the second child to Jewish–Georgian parents, with nomaternal or family history of thrombosis or autoimmunity. Preg-nancy and delivery were uneventful; he was born at 40 weeks ofgestation weighing 3730 g. Perinatal history was unremarkableaside from diagnosis of developmental dysplasia of the hip (DDH).Upon arrival to the ER he had normal temperature, but a few hours

Table 1In a case of de novo APS, 14 months of biochemical follow-up

9–33 days 3.5 months 6 months 8 months 14 months

WBC (103/l) 40.9 16.9 NA 11.6 NAHemoglobin (g%) 6.5 10.6 NA 10.8 NAPlatelets (109/l) 22/1378 526 NA 441 NAESR (mm/h) 140 NA NA NA NACRP (mg%) 22 NA NA NA NAPT (60–100%) 45.5 NA 95 96 74PTT (25–40 s) 56a NA 44.6a 48.8a 47.1a

Antiphospholipid antibodiesLAC Negative NA Negative Negative PositiveaCL IgG (o10 U/ml) Negative NA 23.13 15.46 NegativeaCL IgM (o7 U/ml) 7.69 NA Negative Negative Negativeanti-β2GP1 IgG (o5 U/ml) Negative 10.8 Negative 30.33 9.5anti-β2GP1 IgM (o5 U/ml) 21.13 Negative 18.52 Negative NegativeANA NA NA Negative NA NA

Results in the first column represent extreme values during hospitalization.aCL—anti-cardiolipin antibody, aβ2GP1—anti-β2-glycoprotein1 antibody, CRP—C-reactive protein, ESR—erythrocyte sedimentation rate, LAC—lupus anti-coagulant, NA—notapplicable, PT—prothrombin time, PTT—partial thromboplastin time, WBC—white blood count.

a Prolonged PTT reflects the presence of circulating anticoagulants.

O. Gordon et al. / Seminars in Arthritis and Rheumatism ] (2014) ]]]–]]]2

later he developed a fever of 38.81C. Laboratory evaluationrevealed metabolic acidosis and acute renal failure, both resolvedgradually following fluid resuscitation. Urine was positive forleukocytes. Blood cultures repeatedly grew E. coli. A urine culturewas obtained but due to a technical error did not yield any results.This infection was considered urosepsis and was treated as such.D-dimer was elevated (49 mg/ml). Doppler ultrasound (DUS)demonstrated deep vein thrombosis (DVT) of the left leg involvingthe popliteal veins, common femoral vein, and extending up to theleft external iliac vein, without involvement of the inferior venacava (IVC) or the renal veins. Table 1 specifies laboratory resultsduring hospitalization and follow-up.

He was admitted to the pediatric intensive care unit and treatedwith fluids, antibiotics, and intravenous unfractionated heparin,later replaced with low-molecular-weight heparin (LMWH). Echo-cardiography demonstrated normal cardiac structure and functionand only mild peripheral pulmonary stenosis (PPS). Thrombophiliaworkup included protein C 22%, protein S 56.3%, antithrombin 56%,and homocysteine, all of which were normal for age. Protein Clevel, repeated at 3.5 months, increased to 78%. No mutations werefound for factor V Leiden or prothrombin. At the age of 16 days,tests revealed positive aPL antibodies that remained positiveduring a follow-up of 14 months. Table 1 specifies the antibodiestested. In brief, aCL was positive in a low titer (range: 8–23 U/ml)and anti-β2GP1 was positive for both IgM and IgG intermittently(range: 9.5–30.33 U/ml). The LAC assay gave borderline results andwas either negative or positive. The mother was tested and wasfound negative for aPL antibodies, including LAC, aCL, and aβ2GP1.Because of thrombocytopenia and renal failure, a test forADAMT13 was performed to exclude congenital thromboticthrombocytopenic purpura (TTP) and was found to be normal.Later during the same hospital stay, left elbow swelling was notedtogether with reduced range of motion. An X-ray demonstratedperiosteal elevation in the left distal humerus, indicating osteo-myelitis, for which he was fully treated.

At 6 months, a DUS demonstrated complete resolution of DVT.He then underwent corrective surgery for DDH and was placed in aSpica cast. No recurrent thrombosis has occurred under LMWHtreatment up to the current age of 14 months.

Review of cases

We conducted an exhaustive search of the literature for cases ofneonatal APS using PubMed by the key words “neonatal” or

“perinatal” together with “antiphospholipid antibody or syn-drome.” We found 33 cases [11–21], of which 10 represent thede novo occurrence of APS on the basis of the following criteria:(1) Neonatal presentation of thrombosis. (2) Positive aPL anti-bodies. (3) Negative aPL antibodies in the mother or cord bloodand/or positive non-penetrable antibodies, such as IgM. Wegathered missing information by personal communication withthe respective authors or excluded cases with limited information.Together with the case reported herein, we review 11 casesfulfilling the detailed criteria (Table 2).

Maternal history

Only in 1 case maternal history was positive for APS (case 2)and later for SLE. This case was considered de novo because theneonate had positive IgM aCL antibodies. While it is accepted thatAPS is an acquired and not an inherited disorder, it cannot beconcluded whether maternal lupus in this case contributed to theclinical course and poor outcome.

Thrombosis and clinical course

Clinical symptoms of thrombosis were observed from 20 h afterbirth to 17 days after birth. Arterial thrombosis was evident in8 cases, all of which were acute ischemic stroke (AIS). Two caseswere of DVT (cases 2 and 11). One case reported mixed arterial andvenous thrombosis (case 8). Mortality was noted in only 1 casethat died soon after presentation due to refractory septic shock(case 2). To the best of our understanding, this death was notattributed to the thrombotic event.

Antiphospholipid antibodies

The time of identification of positive aPL antibodies variedbetween few days after birth and up to 13 months. In 5 of the cases(cases 7–11), repeated aPL serum analysis was performed andrevealed that aPL antibodies remained positive as long as testedfor during follow-up (mean follow-up was 2.8 years; range:14 months to 5 years).

Associated manifestations

In the consensus statement for the revised Sapporo criteria,other non-thrombotic features associated with APS are detailed [7],

Table 2Eleven cases of de novo neonatal APS

Case References Clinical course Location of thrombosis Neonatal antibodies Maternalantibodies

Additionalthrombotic riskfactors

Family history Treatment andfollow-up

1 Ebelinget al. [16]

Term baby. Seizures in day 2 oflife diagnosed as ischemic stroke.

Right temporoparietaland left parietalinfarctions.

aβ2GP1 IgG. Tested at theage of 9 months. Noother aPL antibodiestested.

Negative NA NA At 9 months, left spastichemiparesis and normal mentaldevelopment. Treatmentunknown. No recurrence.

2 SoaresRolimet al. [21]

Twin 1: 35 WG. 2410 g. At 20 hafter birth developed respiratorydistress and was ventilated.Presented with thrombocytopenia,livedo reticularis, and edema ofthe face and the thorax, diagnosedas DVT. Developed refractory septicshock and death. Twin 2: healthyboy, negative for aPL antibodies.

Left subclavian andexternal jugular veins.

aCL IgG and IgM. NegativeANA. Tested at 1 month.

aCL IgG, LAC, ANA,and anti-ds-DNA.

Infection. Venousdissection andplacement of acentral veincatheter.

Mother diagnosedwith APS and afterdelivery with SLE.

UFH, IVIG.

3–6 Berkun et al.(2006).4 cases.

NA Ischemic stroke in all4 cases.

LAC in all 4 patients. aCLIgM in 2, aCL IgG in 1,and aβ2GP1 in 2.

Two mothers werenegative for aPL.Two were nottested.

One patient with FVLand prothrombinheterozygosity.Another withMTHFRpolymorphism.

No One patient received indefiniteanticoagulation due topersistence of LAC andcombination of FVL andprothrombin heterozygosity.No new events in a meanfollow-up of 7.4 years.

7 Alshekailiet al. [20]

Term baby. At 4 days presentedwith reduced movements on rightlimbs. At 6 months suffered fromseizures, then diagnosed withischemic stroke.

Left middle cerebralartery infarction.

aCL and aβ2GP1 IgG. Lowtiter of ANA. Negative forLAC. First tested at the ageof 6 months. Positive aPLantibodies persisted forat least 4 years.

Negative. Cord bloodwas also negative.

FVL heterozygosity. No Anticoagulation. During 4 yearsof follow-up he developedlivedo reticularis but there wereno new thromboembolic events.

8 Cabral et al.(2011)

36 WG. At 17 days presented withabdominal distension, bloodystool, and septic shock. Exploratorylaparotomy and subsequenthistopathology revealed smallbowel infarction. After a period ofhypotension, he developedhematuria, refractory hypertension,and renal failure with an atrophicright kidney. Right nephrectomy wasperformed and hypertensionstabilized. Pathology revealed renalvein thrombosis.

Small bowl infarction.Renal vein thrombosis.

aCL, aβ2GP1 IgG, and IgM.ANA. Negative for LAC.Tested at 13 months.Positive aPL antibodiespersisted for at least5 years.

Negative Infection,heterozygosity forprothrombin20210G4A, andhomozygosity forPAI-1 675G4A.

No At 13 months, seizures andright hemiparesis diagnosed asstroke. Aspirin was started. 20days later developed lefthemiparesis, axial weakness,and right eye exophoria.Diagnosed with multiple denovo infarcts. LMWH added.Follow-up at 5 years, noadditional thrombotic eventswhile on LMWH.

9 Merlin et al.[18]

Pregnancy complicated by diabetes.39 WG. 3830 g. On day 3 exhibitedright hemicorporeal clonic seizures.

Infarction in thesuperficial territory ofthe left middlecerebral artery.

aCL IgG and aβ2GP1 IgG.Negative for LAC. Firsttested at the age of 5days, but positive aPLwas first detected at theage of 1 year. Positive aPLantibodies persisted for atleast 2.5 years.

Negative. Cord bloodwas also negative.

Pregnancycomplicated bydiabetes.Lipoprotein(a) level f41 mg/dl (N o 30).PC activity 68% ofcontrol (N 4 70).

No Aspirin. After 3.5 yearsdevelopmental and neurologicalexamination were normal, withno thrombotic or epilepticrecurrence.

10 Sousa et al.[17]

40 WG. At 8 h, multifocal clonicseizures and left-sided hemiparesis.

Infarction of the rightcaudate and lenticularnuclei with extension

LAC, aCL IgG, and aβ2GP1IgG. Negative for aCL andaβ2GP1 IgM first detected

Negative Homozygous 1298C/CMTHFR, double-homozygous PAI-1

No Aspirin. At 12 months, left sidestrength improved. No furtherseizures or thrombosis. Did not

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Table

2(con

tinu

ed)

Case

Referen

ces

Clin

ical

course

Location

ofthrombo

sis

Neo

natal

antibo

dies

Maternal

antibo

dies

Additional

thrombo

ticrisk

factors

Family

history

Trea

tmen

tan

dfollo

w-up

MRIreve

aled

acute

isch

emic

stroke

.MRan

giog

raphy

was

normal.

tothecerebral

ped

uncle.

attheag

eof

3mon

ths.

At9mon

ths,

positiveLA

C,

aCLIgG,a

ndds-DNA

antibo

dy.

844A

/Aan

d67

54G

/4G

dev

elop

other

clinical

orlabo

ratory

man

ifestation

forSL

E.

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treport

40W

G.3

730g.

At9day

spresented

withdeh

ydration

anded

emaof

the

left

leg.

Diagn

osed

withE.

colisepsis

andleft

legDVT.

Thrombo

cytopen

iazatpresentation

.Later

seve

rethrombo

cytosis.

At2wee

kspresented

withleftelbo

wsw

ellin

gan

ddiagn

osed

withosteom

yelitis.

Poplitea

lve

ins,

common

femoral

vein,

extendingupto

the

left

extern

aliliac

vein.

aβ2G

P1IgM

andlaterIgG.

Positive

aCLIgG.

Borderlin

eaC

LIgM.

Neg

ativeforLA

Can

dANA.

Firsttested

attheag

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16day

s.Po

sitive

aPL

antibo

diespersisted

forat

least14

mon

ths.

Neg

ative

Infection,D

ehyd

ration

No

UFH

andlaterLM

WH.A

t14

mon

thsstill

onan

tico

agulation

andwithclinical

improve

men

t.Nothrombo

ticrecu

rren

ce.

aCL—

anti-cardiolip

inan

tibo

dy,aβ

2GP1

—an

ti-β2-glycop

rotein1an

tibo

dy,

ANA—an

ti-n

uclea

ran

tibo

dy,

DVT—

dee

pve

inthrombo

sis,FV

L—factor

VLe

iden

,LAC—lupusan

ti-coa

gulant,LM

WH—low-m

olecular-weigh

thep

arin,M

THFR

—

methy

lenetetrahy

drofolate

reductase,

MRI—

mag

netic

resonan

ceim

aging,

NA—not

available,

PAI-1—

plasm

inog

enactiva

torinhibitor-1,U

FH—unfraction

ated

hep

arin,W

G—wee

ks'g

estation

.

O. Gordon et al. / Seminars in Arthritis and Rheumatism ] (2014) ]]]–]]]4

including heart valve disease, livedo reticularis, thrombocytopenia,nephropathy, and neurological manifestation. These features arenot specific and were not included in the revised criteria; however,it was recognized that they are frequently associated with APS.Thrombocytopenia was manifested in 2 cases (cases 2 and 11) andlivedo reticularis in 2 cases (cases 2 and 7), one of which wasduring follow-up (case 7). APS is closely related to SLE, and SLEpatients are at an increased risk for developing APS. Antinuclearantibody (ANA) was positive in 2 cases (cases 7 and 8), but nodiagnosis of neonatal SLE was made.

Additional thrombotic risk factors

All cases reported additional risk factors other than APS,excluding 1 report with missing information (case 1). Acquiredrisk factors included infection (3/10; all of which developedsepsis), central vein catheter (1/10), dehydration (1/10), and gesta-tional diabetes (1/10). Congenital risk factors included FVL hetero-zygosity (2/10), prothrombin heterozygosity (2/10), MTHFRmutation (2/10), homozygosity for PAI-1 mutation (2/10), andelevated lipoprotein(a) levels (1/10).

Prognosis and treatment

Much of the information on treatment is missing. In the acutephase, intravenous unfractionated heparin, LMWH, or aspirin wereused depending on the clinical manifestations. At least 5 patientswere treated with long-term anticoagulation with either LMWH oraspirin, some because of persistent aPL antibodies. Only 1 casereported recurrent thrombotic events (case 8). In this case, nopreventive treatment was administered before the first recurrence,and the second recurrence accrued despite aspirin therapy.

Discussion

Several specific features have emerged distinguishing mater-nally transmitted APS from de novo neonatal APS and emphasizingthe clinical implications of the latter. In de novo neonatal APS,diagnosis was delayed and the mean time for diagnosis was4.7 months (median ¼ 3 months, range: 5 days to 13 months).This may probably be explained by the low awareness of cliniciansto this rare condition together with the fact that no family ormaternal history was noted in all cases accept one (case 2). Incomparison, in maternally transmitted APS, almost 40% of mothershad a diagnosis of APS prior to delivery and others had anobstetrical history of multiple miscarriages. The mean time fordiagnosis was 2.2 months (median ¼ 11 days, ranges fromimmediately after birth to 14 months later) [12–15]. Associatedmanifestations of APS were noted in de novo disease, such aslivedo reticularis and thrombocytopenia, although the last mightbe explained as a manifestation of sepsis (cases 2 and 11). Whenrepeatedly tested, aPL antibodies remained positive on follow-upin cases of de novo APS (mean follow-up was 2.8 years, range: 14months to 5 years) and no report stated clearance of aPL anti-bodies. When tested, most cases showed positive aPL antibodies of2 or 3 different types, sometimes with alternating aPL antibodieswhen tested over time. It is difficult to conclude the persistence ofaPL antibodies in maternally transmitted APS. In many of thereported cases, follow-up was incomplete and, in fact, in somecases the diagnosis relies on maternal positivity alone. In the casesthat did report biochemical follow-up, 1 case stated clearance ofLAC by 9 days after delivery, and 5 more cases reported positiveantibodies up to 14 months after delivery (mean ¼ 7 months,range: 1–14 months) [12–15]. In a study that tested for aPL in

O. Gordon et al. / Seminars in Arthritis and Rheumatism ] (2014) ]]]–]]] 5

healthy infants born to mothers with APS, it was evident that atleast aCL is negative in all infants at 12 months [22].

It is important to note whether aPL antibodies were trans-mitted or produced de novo, in almost all cases additionalthrombotic risk factors were diagnosed. These included inheritedthrombophilia as well as acquired thrombotic risk factors, such asinfection, central vein catheter, asphyxia, dehydration, and gesta-tional diabetes. In both maternally transmitted and de novo APS,most of the cases were of arterial thrombosis, mainly AIS. Treat-ment of neonatal thrombosis is difficult, and there is poor knowl-edge regarding bleeding risks associated with treatment and long-term morbidity and outcome of untreated thrombosis [23,24]. Inthe cases presented here, much of the information regardingtreatment is missing and no preferred treatment option is noted.

There is a close relation between viral or bacterial infection andthe presence of aPL antibodies as first demonstrated by thedetection of aCL antibodies in syphilis [9]; however, in bothbacterial and viral infection the aPL antibodies are usually notpersistent, and the mere presence of aPL antibodies do notnecessarily lead to thrombosis [25–27]. Therefore, the associationbetween thrombosis and the persistence of aPL antibodies overtime is, in our opinion, a key element in the diagnosis of denovo APS.

Given the multifactorial pathogenesis of neonatal thrombosis, itis difficult to present definitive recommendations regarding labo-ratory testing for the presence of a thrombophilic state. Currentlyavailable guidance for thrombophilia testing for neonates andchildren is largely based on expert opinion [28]. Diagnosticthrombophilia testing is suggested for the first unprovoked andrecurrent neonatal thrombotic event. The core set of thrombo-philia workup includes tests for protein C activity, protein S-freeantigen level, antithrombin activity, activated protein C resistance,prothrombin gene mutation, factor V Leiden gene mutation, andaPL antibodies. Results of protein C, protein S, and antithrombinshould be interpreted according to neonatal age-, analyzer-, andreagent-specific reference ranges and the diagnosis of inheritedstates [29]. Anticoagulation, specifically vitamin K antagonists,may affect the interpretation of thrombophilia testing. Screeningfor protein levels and LAC in patients treated with LMWH ispossible [28,30].

Conclusions

De novo neonatal APS is a newly defined and rare condition,which in the existence of additional thrombotic risk factors maylead to substantial morbidity and mortality. To date, only a fewcases have been reported, probably reflecting under-diagnosis.Information regarding the clinical course and the treatmentoptions should be gathered and explored more extensively. Basedon the current analysis we suggest that de novo APS be consideredand tested for in all cases of unexplained neonatal thrombosis,aiming at early diagnosis and implementation of long-term anti-coagulation to prevent recurrent thrombotic events.

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