Clinical vignettes

1. Obstetric APS (real APS without thrombosis)

A 28‐year‐old G2P0110 seeks your advice regarding another pregnancy. Her first pregnancy ended in an early miscarriage at eight weeks gestation. In her second pregnancy, she developed severe pre‐eclampsia at 21 weeks gestation. Fetal demise was diagnosed the day of admission for induction. The stillborn fetus was morphologically normal and was small‐for‐gestational age. Tests for LAC were positive on the day of admission for induction and again three months later. The IgG anticardiolipin was 62 units on admission and 47 units three months later. She has no other important past medical or surgical history.

1. 2. Thrombotic APS (APS with thrombosis)

At 33‐year‐old nulligravida has a history of pulmonary embolism two years ago after taking combination oral contraceptives for several months. Her hematologist found her to be positive for LAC and high‐titer IgG and IgM anticardiolipin and anti‐β₂‐glycoprotein 1 antibodies at the time of presentation with pulmonary embolism and on two other occasions since. She has been on long‐term anticoagulation with warfarin since her thrombotic event. She would like to know the risks entailed in taking on a pregnancy and how you would manage her anticoagulation therapy during pregnancy.

1. 3. Concerning for APS, but laboratory confirmation pending

You are consulted regarding the management of a 29‐year‐old secundigravida whose first pregnancy was delivered at 33 weeks because of worsening placental insufficiency characterized by fetal growth restriction and oligohydramnios. The infant was small‐for‐gestational age, but is currently alive and well at three years of age. Testing done at the time of her delivery found the patient to be negative for LAC. IgG and IgM anticardiolipin results were 36 units and 53 units, respectively. IgG and IgM anti‐β₂‐glycoprotein 1 results were 21 units and 33 units, respectively. These have not been repeated. The patient is now 12 weeks gestation.

1. 4. Infertility and early miscarriage with atypical antiphospholipid laboratory test results

A 37‐year‐old G3P1021 infertility patient is seeking your advice regarding her recent diagnosis of antiphospholipid syndrome by her infertility specialist. After having an uncomplicated first pregnancy eight year ago, the patient has had an early miscarriage <10 weeks gestation 18 months ago. Her past medical history is unremarkable, though she has a BMI of 34. Because of not becoming pregnant within the last 8 months, she went to see an infertility specialist. Her evaluation included an “antiphospholipid panel.” The results of this panel shows that she is “low positive” for IgM antiphosphatidylinositol and antiphosphatidylserine antibodies and “moderate positive” for IgM antiphosphatidylethanolamine antibody. She is negative for anticardiolipin and was apparently not tested for LAC or anti‐β₂‐glycoprotein 1 antibodies. Her infertility specialist has told her that she has antiphospholipid syndrome and must take a heparinoid during her next pregnancy.

Clinical questions

• What are the clinical presentations of APS?

APS may be diagnosed as a primary condition or may occur in a patient with other autoimmune disease(s), including systemic lupus erythematosus (SLE). Although the exact incidence and prevalence are not known, expert opinion holds that primary APS is about half as common as SLE. Population studies of APS are complicated by the misdiagnosis of patients with non‐diagnostic, low titer positive tests for one or more of the three well‐recognized antiphospholipid antibodies (aPL). Up to 5% of healthy women [2, 3] and up to 40% of patients with SLE [4] will test “positive” for aPL, though in some cases these will be at titers below the international criteria threshold for diagnosis. In the absence of clinical criteria, the risks associated with an incidentally‐discovered positive aPL test are unknown; a diagnosis of APS should not be made on the basis of such results.

The diagnosis of definite APS [1] requires one or more episodes of thrombosis (arterial or venous) or one or more of the following pregnancy complications:

• Three or more otherwise unexplained recurrent early miscarriages (REMs) (anembryonic or embryonic losses <10 weeks gestation),
  
• One or more otherwise unexplained fetal deaths (≥10 weeks gestation),
  
• One or more preterm births occurring at less than 34 weeks gestation secondary to severe pre‐eclampsia or placental insufficiency.
  
• Recurrent Early Miscarriage. Although some studies suggest that up to 15% of women with REM test positive for aPL [5, 6], the studies are limited by poor standardization of assays, inclusion of women with other causes of REM (e.g. chromosome translocations or uterine anomalies), inconsistent definitions of aPL positivity and recurrent miscarriage (differing number of losses and gestational ages), variable selection of controls, and even different isotypes of aPL tested. That said, authorities generally agree that a woman with three or more otherwise unexplained REMs and a repeatedly positive aPL result according to the international criteria have APS. However, authorities disagree regarding the frequency of APS among women with REM, with some groups finding very few cases of REM meeting international laboratory criteria [7, 8]. Experts also disagree about whether or not a woman with REM and either non‐criteria aPL (e.g. a single positive test or a low titer result) or a positive result in a non‐standardized assay has APS or “non‐criteria” APS. This debate certainly would apply to our clinical vignette #4 [9-11].
  
• Fetal Death. Several recent large studies have examined the relationship between APS and fetal death. The Stillbirth Collaborative Research Network (SCRN) was a multicenter, population‐based case‐control study of stillbirths and life births [12]. In women who suffered a fetal death at or beyond 20 weeks of gestation, the investigators identified aPL (aCL or aβ2‐GP‐I antibodies) in 9.6%. Six percent of women with live births tested positive. When other causes of fetal death were excluded (e.g. fetal anomalies) in a strictly‐applied algorithm, positive aPL tests were associated with an increased risk of fetal death two to five times greater than controls. Specifically, IgG aCL, IgM aCL, and IgG aβ2‐GP‐I antibodies were associated with five‐, two‐, and threefold increased odds of fetal death, respectively. The authors concluded that about 14% of unexplained fetal deaths were likely secondary to APS. Though prospective in nature and detailed in terms of the evaluation of stillbirth, this study was flawed by the lack of repeat testing. The Nimes Obstetricians and Hematologists – Antiphospholipid Syndrome (NOH‐APS) study [13] was a prospective study of women with well‐characterized APS, including repeatedly positive aPL results. Despite standard treatment in a next pregnancy, women who had a history of a prior fetal death or REM suffered a 16% and 8% fetal loss rate, respectively.
  
• Preterm Delivery for Pre‐eclampsia or Placental Insufficiency. In spite of it being one of the obstetric clinical criteria for the diagnosis of APS, the association between aPL and preterm delivery secondary to placental insufficiency or severe pre‐eclampsia remains ill‐defined, as studies have been limited by variable definitions of placental insufficiency and pre‐eclampsia, possible selection bias, and poor standardization of laboratory tests. Despite these limitations, studies that have examined women with severe pre‐eclampsia suggest that between 5% and 10% of these patients will have positive tests of aPL, as compared to 0.5% of controls [14–17]. The prospective NOH‐APS study found that 10% of women with APS developed severe pre‐eclampsia, despite standard treatment during pregnancy [13]. The relationship between aPL and early delivery for placental insufficiency in the absence of pre‐eclampsia is frankly uncertain. Against this background, most experts agree that the association of aPL with indicated preterm delivery secondary to pre‐eclampsia or placental insufficiency needs further study [11].
  
• Thrombosis. Lower extremity venous thrombosis represents about two‐thirds of thrombotic APS cases and is the most common thrombotic presentation [18]. Recent studies suggest that about 10% of deep vein thrombosis (DVTs) are secondary to APS [19], though this figure varies with the population studied. Stroke is the most common arterial thrombotic presentation, and aPL antibodies are found in up to 20% of ischemic stroke patients under 50‐years‐old [20]. Nephropathy may be the presenting finding in patients with small vessel thrombosis [21]. APS can manifest in diverse and unusual ways including intracranial venous or arterial thrombosis, hepatic venous thrombosis, and intra‐abdominal venous or arterial thrombosis.
  
• Catastrophic APS ( CAPS ). CAPS is a rare but serious presentation of APS. This condition is characterized by rapid‐onset, often small vessel, thrombosis leading to multiple organ failure and has a high mortality rate.
  
• Other Clinical Associations. Although not sufficient to make the diagnosis, other clinical features that may be seen with APS include immune thrombocytopenia, autoimmune hemolytic anemia, cardiac valvular lesions (Libman‐Sachs endocarditis), chronic skin ulcers, false positive rapid plasma reagin (RPR) results, and cognitive impairment [4].
  
• How is the diagnosis of APS made?

Definite APS

International guidelines require one clinical criterion and at least one the presence of at least one repeatedly positive aPL [1]. The clinical criteria for APS are relatively non‐specific and may be due to other factors or etiologies. Thus, the final diagnosis of APS rests on laboratory criteria. The specific laboratory criteria for APS are detailed in Table 31.1. Persistently positive aPL results are required on at least two occasions, at least 12 weeks apart because aPL may be transiently induced by conditions such as infection. Also, misleading or false‐positive results in the LAC assays can occur due to the presence of anticoagulants or poor plasma collection or handling. Experience has shown that aPL immunoassay results for aCL or aβ2‐GP‐I may vary widely. In particular, it is imperative for each laboratory to define an individual titer >99th percentile for aβ2‐GP‐I. Time‐tested, standard calibrators and units for the aCL assay have established, with >40 IgG units (“GPL”) or IgM units (“MPL”) being medium‐ or high‐titer. The clinical significance of IgA aPL antibodies is unclear, and positive titers IgA titers do not currently establish the diagnosis. Most experts avoid checking IgA titers during the clinical evaluation for APS, as their significance is not established and is currently under investigation.

Clinical criteria

Vascular thrombosis a One or more clinical episodes of arterial, venous, or small‐vessel thrombosis in any tissue or organ with thrombosis 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.

Pregnancy morbidity 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, OR One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of eclampsia or severe pre‐eclampsia or placental insufficiency, b OR 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.

Laboratory criteria c Lupus anticoagulant present in plasma, on 2 or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasism, OR Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in medium or high titer (i.e. >40 GPL or MPL, or > the 99th percentile), on at least 2 occasions at least 12 weeks apart, measured by standardized enzyme‐linked immunosorbent assay, OR Anti‐β2 glycoprotein‐I antibody of IgG and/or IgM isotype in serum or plasma (in titer >the 99th percentile), present in medium or high titer, on at least 2 occasions at least 12 weeks apart, measured by standardized enzyme‐linked immunosorbent assay.

Note that Definite APS is diagnosed if at least one clinical and one laboratory criteria are met.

^a Superficial venous thrombosis is not included in the clinical criteria.

^b Generally accepted features of placental insufficiency include: (i) abnormal or non‐reassuring fetal surveillance test(s), e.g. a non‐reactive non‐stress test, suggestive of fetal hypoxemia, (ii) abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia, e.g. absent end‐diastolic flow in the umbilical artery, (iii) oligohydramnios, e.g. an amniotic fluid index of 5 cm or less, or (iv) a postnatal birth weight less than the 10th percentile for the gestational age.

^c Investigators are strongly advised to classify APS patients in studies into one of the following categories: I, more than one laboratory criteria present (any combination); IIa, LA present alone; IIb, aCL antibody present alone; IIc, anti‐β ₂ glycoprotein‐I antibody present alone.

The assay for LAC involves a series of coagulation‐based tests evaluating in‐vitro clotting times and, if prolonged, isolating aPL as the culprit. The final result is reported as “positive” or “negative.” Positive LAC may portend a worse prognosis than other aPL, with recent studies suggesting that the presence of LAC is associated with worse pregnancy outcomes and a higher risk of thrombosis [19

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