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836 ParT Six Systemic Immune Diseases

TABLE 61.1 revised Sapporo TABLE 61.2 Possible Mechanisms of
Classification Criteria for the antiphospholipid antibody–induced
antiphospholipid Syndrome 1 Thrombosis

Clinical Criteria Endothelial Cells–antiphospholipid antibody
1. Vascular thrombosis a (aPL) interaction
(a) One or more clinical episodes of arterial, venous, or small- Endothelial cell damage or activation (via increased expression of
b
vessel thrombosis, in any tissue or organ. adhesion molecules)
c
2. Pregnancy morbidity: Coexisting antiendothelial antibodies
(a) One or more unexplained deaths of a morphologically normal aPL-induced monocyte adhesion to endothelial cells
fetus at or beyond the 10th week of gestation, or Increased tissue factor expression
(b) One or more premature births of a morphologically normal
neonate before the 34th week of gestation because of Platelet–aPL interaction
eclampsia, severe preeclampsia, or recognized features of Platelet activation
d
placental insufficiency or Stimulation of thromboxane production
(c) Three or more unexplained consecutive spontaneous abortions
before the 10th week of gestation, with maternal anatomical or Coagulation System–aPL interaction
hormonal abnormalities and paternal and maternal chromosomal Inhibition of activation of protein C by the thrombomodulin–thrombin
causes excluded.
complex
Inhibition of activation of protein C via its cofactor protein S
Laboratory Criteria e Interaction between aPL and substrates of activated protein C such as
1. Lupus anticoagulant present in plasma, on two or more occasions factors Va and VIIIa
at least 12 weeks apart, detected according to the guidelines of Interaction between aPL and an annexin V anticoagulant shield
the International Society on Thrombosis and Haemostasis.
2. Anticardiolipin antibody of IgG and/or IgM isotype in serum or Complement activation
plasma, present in medium or high titer (i.e., >40 GPL or MPL, or >
the 99th percentile), on two or more occasions, at least 12 weeks
apart, measured by a standardized enzyme-linked immunosorbent
assay (ELISA).
3. Anti-β 2 glycoprotein-I antibody of IgG and/or IgM isotype in serum bacterial peptides, and heterologous β 2 GPI induces polyclonal
or plasma, (in titer > the 99th percentile) present on two or more aPL and clinical events associated with APS. β 2 GPI polymorphisms
occasions, at least 12 weeks apart, measured by a standardized influence the generation of aPL in individuals but have only a
ELISA.
Definite antiphospholipid syndrome (APS) is present if at least one of weak relationship to the occurrence of aPL-related clinical events.
the clinical criteria and one of the laboratory criteria are met. Persons congenitally lacking β 2 GPI as well as β 2 GPI knock-out
Classification of APS should be avoided if less than 12 weeks or mice appear normal.
more than 5 years separates the positive antiphospholipid antibody In humans, although cross-sectional and prospective cohort
(aPL) test and the clinical manifestation. In studies of populations of studies demonstrate that aPL can predict future thrombosis,
patients who have more than one type of pregnancy morbidity, the pathogenic mechanism remains unknown; more than one
investigators are strongly encouraged to stratify groups of subjects mechanism may be involved (Table 61.2). Because high-titer
according to a, b, or c above.
antibody can persist for years in asymptomatic persons and
a Coexisting inherited or acquired factors for thrombosis are not a reason for excluding because positive aPL tests can precede symptoms for years, it is
patients from APS trials. However, two subgroups of APS patients should be likely that vascular injury and/or endothelial cell activation will
recognized, according to (a) the presence, and (b) the absence of additional risk
factors for thrombosis. Indicative (but not exhaustive), such cases include age (>55 in immediately precede thrombosis in persons bearing the antibody.
men and >65 in women) and the presence of any of the established risk factors for Platelet activation followed by binding of aPL to platelet mem-
cardiovascular disease (hypertension, diabetes mellitus, elevated LDL or low HDL brane phospholipid-bound annexins may initiate platelet adhesion
cholesterol, cigarette smoking, family history of premature cardiovascular disease,
body mass index ≥30 kg/m , microalbuminuria, estimated glomerular filtration rate and thrombosis. Antiphospholipid antibodies can inhibit
2
(GFR) <60 mL/min), inherited thrombophilias, oral contraceptives, nephritic syndrome, phospholipid-dependent reactions in the coagulation cascade,
malignancy, immobilization, and surgery. Thus patients who fulfill criteria should be such as protein C and protein S activation. Interaction between
stratified according to contributing causes of thrombosis.
b A thrombotic episode in the past could be considered as a clinical criterion, provided aPL and an annexin A5 anticoagulant shield is another potential
that thrombosis is proved by appropriate diagnostic means and that no alternative mechanism. Recent studies also demonstrate that aPLs induce
2
diagnosis or cause of thrombosis is found.
c Superficial venous thrombosis is not included in the clinical criteria. cellular activation through receptors such as annexin A2 and
d Generally accepted features of placental insufficiency include (i) abnormal or apoER2, and induce release of microparticles from endothelial
nonreassuring fetal surveillance test(s), e.g., a nonreactive nonstress test, suggestive cells. 6
of fetal hypoxemia; (ii) abnormal Doppler flow velocimetry waveform analysis
suggestive of fetal hypoxemia, e.g., absent end-diastolic flow in the umbilical artery; In experimental animal models, aPLs cause fetal resorption
(iii) oligohydramnios, e.g., an amniotic fluid index of 5 cm or less; or (iv) a postnatal (a proxy for recurrent fetal loss) and increase size and duration
birth weight less than the 10th percentile for the gestational age.
e Investigators are strongly advised to classify APS patients in studies into one of the of trauma-induced venous and arterial thrombi. Inhibiting
following categories: I, more than one laboratory criteria present (any combination); complement activation prevents experimental aPL-induced fetal
IIa, LA present alone; IIb, aCL antibody present alone; IIc, anti-β 2-glycoprotein-I death, and C5 knock-out mice carry pregnancies normally despite
antibody present alone.
the presence of aPL, implying that a complement-mediated
effector mechanism is a requirement for fetal death to occur. 7
The commonly accepted hypothesis regarding the origin of In the “second-hit hypothesis,” a second trigger event (such
aPL states that an incidental exposure to environmental agents, as oral contraceptives or surgical procedures) may be necessary
the antigens of which contain β 2 GPI-like peptides, induces aPL for an asymptomatic aPL-positive individual to develop throm-
5
in susceptible individuals via molecular mimicry. In experimental bosis. Acquired and heritable risk factors for thrombosis may
animal models, passive or active immunization with viral peptides, increase the risk of thromboembolic events in aPL patients.