Primary APS
No associated autoimmune disorder
Secondary APS
Associated with SLE, ITP
Familial APS
Runs in families with a complex inheritance pattern
Catastrophic APS
Multiple-vessel thrombosis – life-threatening
Laboratory Testing (Table 18.2)
Table 18.2
Antibody testing in APS
Antibody type | Subtype |
|---|---|
Anticardiolipin ACL | IgG and IgM |
Antiphospholipid APL | Antiphosphatidylserine |
IgG and IgM | Antiphosphatidylcholine |
Antiphosphatidylethanolamine | |
Cofactors | Anti-beta 2 glycoprotein I |
Antiprothrombin | |
Anti-annexin V | |
Anti-protein C | |
Lupus anticoagulant | PTT, APTT, DRVVT |
Antibody Testing
It is recommended that in APS syndrome both the lupus anticoagulant and the antiphospholipid antibody and/or the anticardiolipin antibody should be tested as they are heterogeneous in nature [3].
Antibody testing in APS syndrome is not simple, as patients may exhibit antibodies to cardiolipin (CL), phospholipids (PL) or to one of the cofactors, beta 2 glycoprotein I (β2GPI) [4], which is a natural anticoagulant protein.
Hence, there are a host of antibodies that can be tested, which add to the cost of testing. Antibodies tested by ELISA may be IgG, IgM or IgA classes alone or in combination. In APS, positive IgG antibodies are diagnostic. IgM antibodies found alone may be transient and may be stimulated by viral infections or drugs described below. They are generally innocuous or non-thrombogenic. Hence it is necessary to repeat antibody titres after 6–12 weeks. The antibody titres are reported as low, medium or high positive.
The antiphospholipid antibodies (aPL) are a group of heterogeneous antibodies of which the most commonly tested are phosphatidylcholine (PC), phosphatidylserine (PS) and phosphatidylethanolamine (PE). In addition phosphatidylglycerol and phosphatidylinositol are also recognized but less commonly used in the clinical setting.
It was realized in 1990 that a positive ELISA test for aCL depends on a protein cofactor, β2GPI, to exert their action and aPL antibodies need this plasma cofactor. They do not bind directly to the anionic phospholipid but to the protein/phospholipids and prothrombin [5].
Hence antibodies to beta 2 glycoprotein I are also diagnostic for APS syndrome. Many additional cofactors have been identified since then, like antiprothrombin, anti-annexin V and anti-protein C and S [5].
Recently antiphosphatidylserine-dependent antiprothrombin antibody (aPS/aPT) has also been detected in these patients [6]. This is a new marker antibody reported in 2006.
The definition of aPL antibody now appears to be an antibody that targets not just phospholipids but also PL-binding proteins. The antibody may react preferentially with the PL-bound form or may bind to the free antigen in plasma as an immune complex (IC) to potentiate binding to a given PL.
Lupus Anticoagulant
Apart from antibody testing by ELISA, these patients test positive for lupus anticoagulant (LA). It tests for derangement of coagulation profile. Contrary to what its name implies, the LA is powerfully thrombotic in vivo. Its name has been derived from the observation that it prolongs all phospholipid-dependent coagulation tests, including the prothrombin time, partial thromboplastin time and Russell viper venom time.
ACL and LA although related antibodies are distinct, and many individuals with aCL do not have LA and vice versa [7]. Although majority of patients are positive for aCL and LA, about 10–16 % are positive for LA and negative for aCL, and 25 % are positive for aCL and negative for LA [8, 9]. Thus it is important to test for both antibodies while investigating for APS.
Mechanism of Pregnancy Loss
APS is associated with very early pregnancy loss, first-trimester miscarriages, second-trimester intrauterine deaths and third-trimester complications like pre-eclampsia, intrauterine growth restriction, oligohydramnios, placental abruption and intrauterine fetal death. It is also associated with neonatal morbidity related to prematurity and growth retardation, like necrotizing enterocolitis, intraventricular haemorrhage and even neonatal deaths.
Pregnancy is a hypercoagulable state. In 1856, the Prussian pathologist Rudolf Virchow first proposed his hypothesis, to explain the pathogenesis of thrombosis [10], which holds true even today. He suggested that three factors were necessary to produce thrombosis:
(i)
Hypercoagulability
(ii)
Stasis
(iii)
Endothelial damage
In pregnancy there is an increase in certain clotting factors leading to hypercoagulability and there is stasis in the pelvic and lower limb veins. There is however no endothelial damage. In APS syndrome endothelial damage is widespread due to antigen-antibody binding and complement activation which adds fuel to the fire and increases the thrombogenic potential manifold. Available data indicate that the thrombogenic function of aPL antibodies involves their general effect on platelets, endothelial cells, anticoagulant mechanisms and fibrinolytic pathways, as well as their local effect on trophoblasts and villi cells, leading to reduction of annexin V (placental anticoagulant protein-I) production and inhibition of its anticoagulant function [11, 12].
Thrombogenic effects of APS in pregnancy include:
Recognition of cofactor beta 2 glycoprotein I on the endothelial cells and trophoblastic surface that allows deposition of aPL antibodies at these sites promoting thrombosis.
Activation of endothelial cells like monocytes and platelets at the antibody-binding site.
Vasculopathy of the spiral arteries of the uterus that are the feeder vessels to the placenta. This leads to placental infarction and thrombosis, which is a triggering factor for pre-eclampsia and intrauterine growth restriction.
In addition APS slows the mechanisms that aid in dissolving intravascular clots like:
Inhibition of natural anticoagulants like protein C and tissue factor pathway inhibitor
Inhibition of fibrinolytic system
All of the above mechanisms increase thrombogenic complications in pregnancy and can also result in arterial and venous thrombosis in pregnancy.
Besides thrombogenesis, APS also exerts harmful non-thrombogenic effects which are as follows:
1.
Antiphospholipid antibodies exert a direct effect on trophoblast function resulting in direct cellular injury and inhibition of syncytia formation, which results in decreased trophoblastic invasion. This will result in trophoblastic dysfunction and account for very early pregnancy losses as well as poor implantation leading to subfertility.
2.
Antiphospholipid antibodies affect human chorionic gonadotrophin secretion by trophoblast cells by abolishing GnRH-induced hCG stimulation of human trophoblastic cells. They also decrease the placental hormone production, secondary to trophoblastic dysfunction [13]. This will account for early and mid-trimester losses.
3.
Recent studies have defined an important inflammatory role of antiphospholipid antibodies with activation of the complement system. RPL may be the result of this inflammatory condition and that complement inhibitors may be the preferred therapy. The efficacy of heparin in APS may rely on its complement inhibitory action as well as its anticoagulant potential. Thus, it is possible that the unifying feature of the many aPL antibodies which have been linked to RPL is the propensity of a given aPL to fix and activate the complement, particularly in an inflammatory setting. Furthermore, the complement in conjunction with specific antibody can elicit a wide array of clinical features, including thrombosis, and therefore may be a common denominator in aPL disorders [14].
It is now well recognized that aPL antibodies exert both thrombogenic and non-thrombogenic detrimental effects on pregnancy in the early mid- and late trimesters and may be implicated in recurrent implantation failures in patients undergoing assisted reproductive techniques (ART).
Indications for Testing
The obstetric clinical criteria for testing had been defined at an international antiphospholipid symposium, held in 1999. These include [15]:
1.
One or more unexplained deaths of a morphologically normal fetus more than 10 weeks of gestation documented by ultrasound or direct examination
2.
One or more preterm births at or before 34 weeks of gestation due to severe pre-eclampsia or placental insufficiency
3.
Three or more consecutive abortions before 10 weeks gestation with no maternal hormonal, anatomic abnormalities, normal maternal and paternal chromosomes and other causes of recurrent losses being ruled out
4.
History of vascular thrombosis:
Unexplained venous thrombosis
Unexplained arterial thrombosis
Small-vessel thrombosis
These criteria have been revised in 2006 at a workshop in Sydney, Australia. The revised criteria are mentioned in Table 18.3 [16].
Table 18.3
Revised classification of APS syndrome
Revised classification criteria for the antiphospholipid syndrome: |
Antiphospholipid antibody syndrome (APS) is present if at least one of the clinical criteria and one of the laboratory criteria that follow are met. |
Clinical criteria |
1. Vascular thrombosis |
One or more clinical episodes of arterial, venous or small-vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (i.e. unequivocal findings of appropriate imaging studies or histopathology). For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall. |
2. Pregnancy morbidity |
(a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus |
(b) One or more premature births of a morphologically normal neonate before the 34th week of gestation because of (i) eclampsia or severe pre-eclampsia defined according to standard definitions or (ii) recognized features of placental insufficiency |
(c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded |
In studies of populations of patients who have more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of subjects according to a, b or c above. |
Laboratory criteria |
1. Lupus anticoagulant (LA) present in plasma, on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Haemostasis (Scientific Subcommittee on LAs/phospholipid-dependent antibodies) |
2. Anticardiolipin (aCL) antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titre (i.e. >40 GPL or MPL or > the 99th percentile), on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA |
3. Anti-β2 glycoprotein I antibody of IgG and/or IgM isotype in serum or plasma (in titre > the 99th percentile), present on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA, according to recommended procedures |
Classification of APS should be avoided if less than 12 weeks or more than 5 years separate the positive aPL test and the clinical event. |
There is currently a debate over screening the high-risk obstetric population for APS [17]. It has been proposed that in patients with history of thrombotic episodes prior to pregnancy or patients with previous thromboembolic episodes during pregnancy or gestational problems likely to be thrombotic in nature, the significant association with predisposing thrombophilic conditions could justify screening for APS syndrome, homocysteine levels and perhaps factor V Leiden mutation, activated protein C resistance (APCR) and antithrombin III deficiency. However routine screening of the general obstetric population is not recommended as it is not cost-effective.
Diagnosis
At least one clinical and one laboratory criteria are required to classify a patient with APS [18]. These must be positive on two occasions 6–12 weeks apart. This is because transient positive results for aPL IgM may occur in the presence of viral infections such as chickenpox, adenovirus, mumps, HIV and also syphilis [19]. Certain drugs such as procainamide, chlorpromazine, sodium valproate, phenytoin, hydralazine and propranolol may induce aPL antibodies which are transient and non-thrombogenic. Because of the heterogeneity of antibodies tested and the fluctuating antibody levels, the diagnosis of APS syndrome is difficult to establish, although once diagnosed the treatment is non-controversial.
Classification of APS (Table 18.1)
Primary APS (PAPS)
Patients with LA or medium-to-high levels of IgG or IgM aCL antibodies and fetal death, recurrent pre-embryonic or embryonic pregnancy loss, thrombosis, or neonatal death after delivery for severe pre-eclampsia or fetal distress.
Secondary APS (SAPS)
Patients with systemic lupus erythematosus (SLE) who have antiphospholipid antibodies (aPL) and or lupus antibodies are classified as secondary APS. There are no major differences in the clinical presentation in primary and secondary APS except that secondary APS has a greater than 40 % risk of thrombosis than those without SLE and conveys a worse prognosis.
Familial APS Syndrome
Goel [20] studied families with more than one affected member, examined possible modes of inheritance and determined linkage to potential candidate genes. In seven families, 30 of 101 family members met the diagnostic criteria for the syndrome. Segregation studies rejected both environmental and autosomal recessive models, and the data fitted best, either a dominant or a codominant model. Linkage analysis showed independent segregation of antiphospholipid syndrome and several candidate genes.
Catastrophic APS (CAPS)
Recently described in 280 patients, catastrophic APS is an uncommon but potentially life-threatening condition that needs high clinical awareness. The first clinical manifestation at the time of the catastrophic episode was a pulmonary complication in 24 % of the cases, a neurologic feature in 18 % and a renal feature in 18 %. During the catastrophic episode, multiple-vessel thrombosis may lead to multi-organ failure. Intraabdominal involvement was identified in the majority of patients, mainly consisting of renal (71 %), hepatic (33 %), gastrointestinal (25 %), splenic (19 %), adrenal (13 %) and pancreatic (8 %) manifestations. One hundred twenty-three (44 %) patients died at the time of the catastrophic APS event, but higher recovery rate was achieved by the combination of anticoagulants plus corticosteroids along with plasma exchange (PE) and/or intravenous immunoglobulins (IVIG) (69 % versus 54 %) [21].
Management
Preconception Counselling
Therapy needs to be started early in pregnancy hence preconception counselling is necessary. In patients with implantation failures and very early pregnancy loss, low-dose aspirin may be started in the preconception period along with folic acid. The need for close surveillance of the pregnancy, with a multidisciplinary approach, should be explained. Delivery should be planned at a centre with advanced neonatal intensive care facilities.
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