Antiphospholipid Antibody Syndrome in Children

Antiphospholipid Antibody Syndrome in Children
By:Jill Glassberg Azok
Grand Rounds
January 23, 2009

Case: OL

* HPI: 2 yo female with Trisomy 21, Tetralogy of Fallot
o 7/9/08: surgical repair of TOF
o 7/31: re-exploration of surgical wound due to wound dehiscense, cultures +pseudomonas
o 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
o 8/15: returned to OR for exploration of sternal wound due to fever, respiratory distress, and rash; no evidence of infection
o 8/22: returned to OR sternal non-union
+ cultures +corynebacterium and enterococcus facaelis


* PMHx
o DOL 3: TE fistula repair
o DOL 9: modified BT shunt
o Post-op course complicated by thrombus in iliac and aorta, requiring thrombectomy
o Hypothyroidism
o Trisomy 21
o Tetralogy of Fallot with pulmonary atresia
o Chronic lung disease requiring tracheostomy and ventilator
Labs
* Lupus anticoagulant: positive
* Russel viper venom test: negative
* Cardiolipin antibody: positive
o IgM: indeterminate, IgA/IgG: negative
* Beta-2-Glycoprotein-I
o IgM: negative, IgA/IgG: positive
* Phosphatidylserine antibodies
o IgA, IgG, IgM-negative
* Skin biopsy
o Marked hemorrhage in the superficial dermis; prominent fibrin thrombi with white blood cells occluding the vessels of the superficial vascular plexus.
o 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.

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
o KUB: pneumatosis with possible portal venous gas formation
o Taken To OR for concern for necrotizing enterocolitis;
o Exploratory laparotomy and ileocolic resection
o Small intestine had diffuse areas of necrotizing enterocolitis with poor perfusion
o Right colon and the transverse colon were distended with evidence of full-thickness injury and vessel thrombosis
o Returned to CICU on inotropic support, broad spectrum antibiotics, both chest and abdomen were open
* 8/28 worsened clinically: Back to OR
o Small bowel was necrotic with multiple areas of full-thickness injury.
o The remaining portion of the colon down to the level of the rectus was also necrotic.
o Thrombi in the distal vessels and at the end branches of the mesenteric vessels
o 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

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

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


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, or

B. 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, or

C. 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 β2-GPI–dependent 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 plasma

C. Shortening or correction of the prolonged coagulation time on the screening test by the addition of excess phospholipid

D. Exclusion of other coagulopathies (eg, factor VIII inhibitor or heparin) as appropriate

Clinical Manifestations
* Vascular thrombosis: arterial and venous
* Skin: Levido reticularis
* Recurrent pregnancy loss
* Neurologic: TIA, stroke, migraine, chorea, seizures, optic neuritis
o 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

Antiphospholipid antibodies
* Antiphospholipid antibodies present in young, healthy controls
o Studies of healthy blood donors
+ Lupus anticoagulant in 8%
+ IgG anticardiolipin in 6.5%
+ IgM anticardiolipin in 9.4%
+ <2% of healthy blood donors with elevated anticardiolipin antibody still had elevated level 9months later
o 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
o Functional assay, measures ability to prolong clotting time
o aPTT, Russel viper venom test, kaolin clotting time
o 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
* 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

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

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

Significance of aPLs
* No history of thrombosis and positive aPL: Risk of new thrombosis <1%
* History of thrombosis and positive aPL: Risk of new thrombosis >10% in first year if anticoagulation stopped within 6 months

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

* Sixteen studies were included (n=1,740)
* 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 <3; 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 >3.0. 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.

Pediatric Antiphospholipid Syndrome: Clinical and Immunologic Features of 121 Patients in an International Registry
* 121 cases of antiphospholipid antibody syndrome in children in the European registry
o Mean age of onset: 10.7 years
o Slightly more common in females, 1.2:1
o 60 (49.5%) had underlying autoimmune disease
o 72 (60%) had venous thrombosis
o 39 (32%) had arterial thrombosis
o 81% had positive anticardiolipin antibodies
o 67% had positive anti-b2-glycoprotein I antibodies
o 72% had positive Lupus anticoagulant

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

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

Catastrophic APS
* Multiple, simultaneous vascular occlusions throughout body
o Widespread microthrombi in multiple vascular bedsMassive thromboembolism
o Clinical involvement of at least 3 organ systems over days to weeks
o Histopathologic evidence of occlusions of small and large blood vessels
o Most common organs: kidney>lung>CNS>heart>skinmultiorgan failure
o DIC in 25%
o 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
o Treat precipitating factor if present
o Anticoagulation
o Steroids
o IVIG
o Plasma exchange
* Mortality > 50%

Antiphospholipid Antibody Syndrome in Children .ppt