Antiphospholipid Antibody Syndrome in Children

1
Antiphospholipid Antibody Syndrome in Children

• Jill Glassberg Azok
• Grand Rounds
• January 23, 2009

2

• I have no financial interests to disclose

3
Case OL

• HPI 2 yo female with Trisomy 21, Tetralogy of
  Fallot
• 7/9/08 surgical repair of TOF
• 7/31 re-exploration of surgical wound due to
  wound dehiscense, cultures pseudomonas
• 7/31 developed rash on buttocks, trunk,
  described as red, circular spots initially
  thought to be Candida
• Over the next 2 wks, developed petechiael rash of
  her trunk, feet
• Rash became diffuse erythroderma with resolution
  of petechiae
• 8/15 returned to OR for exploration of sternal
  wound due to fever, respiratory distress, and
  rash no evidence of infection
• 8/22 returned to OR?sternal non-union
• cultures corynebacterium and enterococcus
  facaelis
• PMHx
• DOL 3 TE fistula repair
• DOL 9 modified BT shunt
• Post-op course complicated by thrombus in iliac
  and aorta, requiring thrombectomy
• Hypothyroidism
• Trisomy 21
• Tetralogy of Fallot with pulmonary atresia
• Chronic lung disease requiring tracheostomy and
  ventilator

4
Labs

• Lupus anticoagulant positive
• Russel viper venom test negative
• Cardiolipin antibody positive
• IgM indeterminate, IgA/IgG negative
• Beta-2-Glycoprotein-I
• IgM negative, IgA/IgG positive
• Phosphatidylserine antibodies
• IgA, IgG, IgM-negative
• Skin biopsy
• Marked hemorrhage in the superficial dermis
  prominent fibrin thrombi with white blood cells
  occluding the vessels of the superficial vascular
  plexus.
• Given the occlusion and lack of inflammation
  around the vessels, we favor the extravasation of
  red blood cells is secondary to the occlusion and
  not secondary to a vasculitis.

5
Hospital Course

• Diagnosed with Catastrophic Antiphospholipid
  Antibody Syndrome Treated with IVIG 5mg/kg
• 8/26 Decreased perfusion, increased lactate,
  decreased urine output, firm abdomen, guaic
  positive stools
• KUB pneumatosis with possible portal venous gas
  formation
• Taken To OR for concern for necrotizing
  enterocolitis
• Exploratory laparotomy and ileocolic resection
• Small intestine had diffuse areas of necrotizing
  enterocolitis with poor perfusion
• Right colon and the transverse colon were
  distended with evidence of full-thickness injury
  and vessel thrombosis
• Returned to CICU on inotropic support, broad
  spectrum antibiotics, both chest and abdomen were
  open
• 8/28 worsened clinically Back to OR
• Small bowel was necrotic with multiple areas of
  full-thickness injury.
• The remaining portion of the colon down to the
  level of the rectus was also necrotic.
• Thrombi in the distal vessels and at the end
  branches of the mesenteric vessels
• She had a complete colectomy with resection of
  most of her small bowel
• 8/29 family decided to withdraw care patient
  expired
• Autopsy Cause of death listed as catastrophic
  antiphospholipid antibody syndrome

6
Antiphospholipid Antibody Syndrome

• Multisystem autoimmune disease
• Most common cause of acquired thrombophilia
• History
• 1906 antiphospholipid antibody discovered in
  patients with syphilis, complement-fixing
  antibody that reacted with extracts from bovine
  hearts
• 1952 Conley and Hartmann described circulating
  anticoagulant in patients with Lupus
• 1963 Bowie associated the anticoagulant with
  thromboembolic events
• Epidemiology
• Most common in young to middle-age adults
• Can occur in children and elderly
• More common in females

7

• Diagnosis
• At least one antiphospholipid antibody
• At least one clinical manifestation
• May be primary or secondary

8
Sapporo Criteria, 1998

• CLINICAL CRITERIA
• 1. Vascular thrombosis One or more clinical
  episodes of arterial, venous, or small vessel
  thrombosis, in any tissue or organ.
• 2. Pregnancy morbidity
• A. One or more unexplained deaths of a
  morphologically normal fetus at or beyond the
  tenth week of gestation, with normal fetal
  morphology documented by ultrasound or by direct
  examination of the fetus, orB. One or more
  premature births of a morphologically normal
  neonate at or before the thirty-fourth week of
  gestation because of severe preeclampsia or
  eclampsia, or severe placental insufficiency,
  orC. Three or more unexplained consecutive
  spontaneous abortions before the tenth week of
  gestation, with maternal anatomic or hormonal
  abnormalities and paternal and maternal
  chromosomal causes excluded
• LABORATORY CRITERIA
• 1. aCL of IgG and/or IgM isotype in blood,
  present in medium or high titer, on two or more
  occasions at least 6 weeks apart, measured by a
  standardized ELISA for ß2-GPIdependent
  aCL.2. Lupus anticoagulant present in plasma,
  on two or more occasions at least 6 weeks apart,
  detected according to the guidelines of the
  International Society on Thrombosis and
  Hemostasis (Scientific Subcommittee on Lupus
  Anticoagulant/Phospholipid-Dependent Antibodies),
  in the following steps
• A. Prolonged phospholipid-dependent coagulation
  demonstrated on a screening test (eg, activated
  partial thromboplastin time aPTT, kaolin
  clotting time, dilute Russell's viper venom time,
  dilute prothrombin time, Texarin
  time)B. Failure to correct the prolonged
  coagulation time on the screening test by mixing
  with normal platelet-poor plasmaC. Shortening
  or correction of the prolonged coagulation time
  on the screening test by the addition of excess
  phospholipidD. Exclusion of other
  coagulopathies (eg, factor VIII inhibitor or
  heparin) as appropriate

9
Clinical Manifestations

• Vascular thrombosis arterial and venous
• Skin Levido reticularis
• Recurrent pregnancy loss
• Neurologic TIA, stroke, migraine, chorea,
  seizures, optic neuritis
• Sneddon Syndrome stroke, levido reticularis,
  hypertension
• Cardiac Coronary artery disease, premature
  atherosclerosis, vegetations
• Renal thrombotic microangiopathy, renal vein
  thrombosis, renal infarction, renal artery
  stenosis with hypertension, increased allograft
  vascular thrombosis, and reduced survival of
  renal allografts
• Pulmonary PE, pulmonary hypertension
• GI Budd-Chiari syndrome, intestinal ischemia
  and infarction, colonic ulceration, esophageal
  necrosis and perforation, hepatic infarction,
  acalculous cholecystitis with gallbladder
  necrosis, and mesenteric and portal vein
  thrombosis
• Hematologic thrombocytopenia, TTP/HUS,
  hemolytic anemia

10
Antiphospholipid antibodies

• Antiphospholipid antibodies present in young,
  healthy controls
• Studies of healthy blood donors
• Lupus anticoagulant in 8
• IgG anticardiolipin in 6.5
• IgM anticardiolipin in 9.4
• lt2 of healthy blood donors with elevated
  anticardiolipin antibody still had elevated level
  9months later
• Incidence increases with age and coexisting
  chronic disease
• Among patients with thrombosis, prevalence of
  antiphospholipid antibodies is 4 to 21
• Increasing risk of thrombosis among those with
  higher antibody titers
• Lupus anticoagulant most specific
• Functional assay, measures ability to prolong
  clotting time
• aPTT, Russel viper venom test, kaolin clotting
  time
• Meta-analysis showed the odds ratio of lupus
  anticoagulant for stroke 11 compared to 1.6 for
  anticardiolipin
• Anticardiolipin antibodies- most sensitive
• Anti-b2 Glycoprotein I antibodies
• Other antibodies of unclear significance
  prothrombin, annexin V, phosphatidylserine,
  phosphatidylinositol, phosphatidylcholine

11

• Some anti-cardiolipin antibodies require presence
  of the plasma phospholipid-binding protein b
  2-glycoprotein I in order to bind to cardiolipin
• People with syphilis or infectious diseases,
  antibodies bind directly to anticardiolipin,
  independent of /inhibited by b 2-glycoprotein-I
• Autoimmune anticardiolipin antibodies directed
  against phospholipid-binding protein, not
  phospholipid itself

12
Pathogenesis Theories

• Interfere with phospholipid-binding proteins
  involved in the regulation of the clotting
  cascade?procoagulant
• Activation of endothelial cells?increased
  expression of cell-surface adhesion molecules and
  increased secretion of cytokines and
  prostaglandins
• Oxidant-mediated injury of vascular endothelium
• Platelet activation

13
Levine, NEJM, 2002
14
Drug Induced aPLs

• Mediations reported
• Phenothiazines
• Phenytoin
• Hydralazine
• Procainamide
• Quinidine
• Dilantin
• Ethosuximide
• Alpha-interferon
• Amoxicillin
• Chlorothiazide
• Oral contraceptives
• Propranolol
• Usually transient
• Associated with IgM
• Rarely associated with thrombosis
• Mechanism unknown

15
Significance of aPLs

• No history of thrombosis and positive aPL Risk
  of new thrombosis lt1
• History of thrombosis and positive aPL Risk of
  new thrombosis gt10 in first year if
  anticoagulation stopped within 6 months

16
A systematic review of secondary
thromboprophylaxis in patients with
antiphospholipid antibodiesRuiz-Irastorza G
Database of Abstracts of Reviews of Effects 2008

• Sixteen studies were included (n1,740)
• Thrombosis recurrence rates among untreated
  patients 19 to 29 per year
• Rates of major bleeding varied widely, ranging
  from 0.57 to 10 per year. Seventy-four per cent
  of bleeding episodes occurred in patients with an
  INR 3.0
• Eighteen deaths were reported to be directly
  related to recurrent thromboses and one due to
  bleeding. Ten patients in one study died as a
  result of the presenting thrombosis
• Patients with definite APS and arterial and/or
  recurrent thrombosis are at high risk of
  recurrent events. Most thrombotic events in
  patients on warfarin occur at an INR lt3
  recurrences are infrequent among those with an
  INR of 3.0 to 4.0. Patients with venous embolism
  or stroke and a single positive aPL that does not
  persist are at relatively low risk of recurrent
  thrombosis.
• Recommendations after a first venous thrombosis,
  patients with APS should be treated with warfarin
  at an INR of 2.0 to 3.0 those with arterial or
  secondary thrombosis should be treated with
  warfarin at an INR gt3.0. Patients with venous
  thrombosis or stroke and a single positive aPL
  test should be retested, and should be treated no
  differently from other patients unless the
  antibody persists. 

17
Lim JAMA 2006
18
Pediatric Antiphospholipid Syndrome Clinical and
Immunologic Features of 121 Patients in an
International RegistryPEDIATRICS Vol. 122 No. 5
November 2008, pp. e1100-e1107

• 121 cases of antiphospholipid antibody syndrome
  in children in the European registry
• Mean age of onset 10.7 years
• Slightly more common in females, 1.21
• 60 (49.5) had underlying autoimmune disease
• 72 (60) had venous thrombosis
• 39 (32) had arterial thrombosis
• 81 had positive anticardiolipin antibodies
• 67 had positive anti-b2-glycoprotein I
  antibodies
• 72 had positive Lupus anticoagulant

19
Unique to Pediatric Population

• Lack of prothrombotic risk factors which are
  present in adults, ie cigarette smoking
• Frequency of vascular thrombosis lower
• Increased incidence of infection-related
  antiphospholipid antibodies
• Parvovirus B19, cytomegalovirus, varicella-zoster
  virus, HIV, streptococcal and staphylococcal
  infections, gram negative bacteria, mycoplasma
  pneumoniae
• Higher frequency of Evans syndrome, Raynauds,
  migraines, and chorea
• Decision-making for long term anticoagulation

20
Neonatal APS

• Due to transplacental passage of maternal aCL,
  disappear over 6months
• In pediatric age group, neonatal period highest
  risk for thrombosis
• Decreased Protein C, Protein S, and antithrombin
• Elevated Factor VIII and von Willebrand factor
• Despite this, very low risk of thrombosis

21
Catastrophic APS

• Multiple, simultaneous vascular occlusions
  throughout body
• Widespread microthrombi in multiple vascular
  beds?Massive thromboembolism
• Clinical involvement of at least 3 organ systems
  over days to weeks
• Histopathologic evidence of occlusions of small
  and large blood vessels
• Most common organs kidneygtlunggtCNSgtheartgtskin?mu
  ltiorgan failure
• DIC in 25
• Respiratory failure, stroke, abnormal liver
  enzymes, renal insufficiency/failure, adrenal
  insufficiency, cutaneous infarcts
• Precipitating factor in 55 Most common is
  infection
• Usually primary APS
• Treatment
• Treat precipitating factor if present
• Anticoagulation
• Steroids
• IVIG
• Plasma exchange
• Mortality gt 50

22

• Asherson R and Cervera R. Catastrophic
  antiphospholipid antibody syndrome. Current
  Rheumatology Rep. 2003 5(5) 395-400.
• Avcin T, Cimaz R, Silverman E, Cervera R,
  Gattorno M, Garay S, Berkun Y, Sztajnbok F, Silva
  C, Campos L, Saad-Magalhaes C, Rigante D, Ravelli
  A, Martini A, Rozman B, Meroni P. Pediatrics.
  Pediatric Antiphospholipid Syndrome Clinical and
  Immunologic Features of 121 Patients in an
  International Registry 2008 122(5) 1100-1107.
• Avcin T. Antiphospholipid syndrome in children.
  Current opinion in rheumatology 2008 20(5)
  595-600.
• Levinne J, Branch W, Rauch J. The
  Antiphospholipid Antibody Syndrome. New England
  Journal of Medicine 2002 346(10) 752-763.
• Lim W, Crowther M, Eikelboom J. Management of
  Antiphospholipid Antibody Syndrome A Systematic
  Review. JAMA 2006 2951050-1057.
• Ravelli A and Martini A. Antiphospholipid
  Antibody Syndrome. Pediatric Clinics of North
  America 2005 52(2)
• Ruiz-Irastorza G, Hunt B, Khamashta M. A
  systematic review of secondary thromboprophylaxis
  in patients with antiphospholipid antibodies.
  Database of Abstracts of Reviews of Effects
  (DARE) December 2008.