ANTIPHOSPHOLIPID SYNDROME James Airoldi

KEY POINTS The diagnosis of antiphospholipid syndrome (APS) requires the presence of at least one clinical and one laboratory criteria. Complications of APS include venous thromboembolism (VTE), early onset preeclampsia, pregnancy loss, fetal growth restriction (FGR), fetal death, preterm birth. Therapy should be : o For APS with 3 unexplained consecutive pregnancy losses at < 10 weeks or > 1 unexplained fetal deaths > 10 weeks: low-dose Aspirin (ASA acetylsalicylic acid) and prophylactic heparin. o For APS with VTE during the current pregnancy: therapeutic anticoagulation. o There are no trials to assess therapy for APS with a history of preeclampsia and/or FGR. All trials on efficacy have used unfractionated heparin as therapy. If on low molecular weight (LMW heparin, regional anesthesia should be delayed until > 24 hours after the last dose.

HISTORIC NOTES Lupus anticoagulant (LA) was first described in early 1950s as prolonging certain clotting assays. A few years later, LA was found to be associated with the false-positive test for syphilis and, paradoxically, thrombosis.

DIAGNOSIS

The diagnosis of antiphospholipid syndrome (APS) requires the presence of at least one clinical and one laborat ory criteria. There are no time limits on the interval between the clinical and laboratory events. Clinical Criteria

Pregnancy loss: > 3 unexplained consecutive pregn ancy losses at <10 weeks, or > 1 unexplained fetal deaths at >10 weeks (morphologically normal fetus). Preterm birth (PTB) at <34 weeks for fetal growth restriction (FGR) or pre-eclampsia: > 1 preterm births at <34 weeks of a morphological]y normal fetus due to severe preeclampsia, FGR, oligohydramnios, abnorm al Doppler flow or NRFHR testing.

Thrombosis: one or more clinical venous, arterial, or small vessel venous thromboembolism (VTE) occurr ing within any tissue or organ. Except for superficial vein thrombosis, thrombosis must be confirmed by imaging or Doppler studies or histopathology.

Laboratory criteria Anticardiolipin antibodies (ACAs): Immunoglobulin G (IgG) and/or immunoglobulin M (1gM) in medium high titers (> 40 units, or> 99th percentile). LA: prolonged activated partial hromboplastin time (aPTT), dilute Russels viper venom time (DRVVT), and kaolin clotting time (Figure 23.1). Anti-2 glycoprotein-I lgG or 1gM antibody (>99th percentile).

Abnormal laboratory tests must occur in > 2 occasions, > 12 weeks apart. Antiphospholipid antibody testing Antiphospholipid antibodies (APAs) are directed against phospholipids, and include ACAs and LA. LA is a double misn omer. LA is seen in many patients without systemic lupus erytheniatosus (SLE), and is associated with thrombosis, not anticoagulation. ACA is strongly correlated with LA and thrombosis. In the 1990s ACAs were found to require the presence of plasma phospholipid-bindingprotein B2 glycoprotein I to bind to cardiolipin. In contrast, ACAs from patients with syphilis or other infections are B2 glyco protein 1 independent. B2 glycoprotein 1 was recently included in the definition. Approximately 80% of patients with LA have ACAs, whereas 20% of patients with ACAs are found positive for LA.2 Substantial inter-laboratory variation when testing the same sera remains a serious problem.

Figure 23.1,Algorithm for interpretation of lupus anticoagulant test:12 aPTT, activated partial thromboplastin time; dRVVT, dilute Russells viper venom time.

SYMPTOMS

Clinical manifestations of APS may involve any organ system, including vascular (arterial or venous), cardiac, cutaneous, endocrine/reproductive, gastrointestinal, hematological, neurological, obstetric, ophthalmological, pulmonary, and renal.

EPIDEMIOLOGY/INCIDENCE APAs are found in up to 5% of healthy controls. The prospective risks in these are unknown. 2535% of SLE patients have APS (see Chapter 24). ACAs are present in 15% of women with recurrent miscarriage; LA is found in 8% of patients with recurrent miscarriage. In women with mid-trimester fetal loss, LA is seen in up to 30%, and 70% of definite APS patients have both ACAs and LA. ETIOLOGY/BASIC PATHOPHYSIOLOGY

APAs may cause pregnancy loss by thrombosis of placental vessels, interference with coagulation factors (reduce levels of annexin V), inhibition of proliferation of trophoblasts, or other yet unknown mechanisms.

CLASSIFICATION

Primary APS -refers to patients with APS but no other autoimmune disorders. Secondary APS refers to patients with othrutoimmune disorders (e.g. SLE). COMPLICATIONS Maternal Venous and arterial thromboembolism (512% risk in pregnancy; 0.52% of asymptomatic people incidentally found to have APAs have thromboses each year); early-onset preeclampsia (placental infarction, decidual vasculopathy); gestational hypertension (1848% of women with APS; this rate is not diminished by aspirin, Heparin, or glucocorticoids); autoimmune thrombocytopenia (4050%); heparin-induced thrombocytopenia (less with low rnolecular weight [LMW] heparin); heparin. induced osteoporosis (especially if on glucocorticoids); lupus flare in patients with coexisting SLE.

Fetal Pregnancy loss; FGR (1530%); fetal death; PTW(33%, secondary to gestational hypertension or placental insuffic iency, either spontaneous or iatrogenic).

PREGNANCY CONSIDERATIONS Complications are less if pregnancy starts when APS is quiescent without symptoms and negative levels of APAs, whereas complications are more frequent and severe if APS is active with high leveLs of APAs. As other autoimmune disorders, APS can exacerbate postpartum: fever, pulmonary infiltrates, pleural effusion, occasionally renal, pulmonary, VTE; rarely disseminated intravascular coagulation (DIC) and mortality. MANAGEM ENT Principles Multidisciplinary management with a rheumatologist or internal medicine specialist is recommended. Screening

Women with the following risk factors should be screened for ACA and LA: o three or more spontaneous unexplained first trimester losses at <10 weeks. o One or more unexplained fetal loss/death at > 10 weeks

o Early-onset (<34 weeks) pre-eclampsia or FGR leading to PTB o SLE o history of vascular thrombosis (VTEs such as deep vein thrombosis [DVT}, pulmonary embolus [PE}, and stroke).

Work-up Laboratory tests as described above (ACA, LA, and anti-2 glycoprotein-I tests). Testing for antiphospholipid antibodies other than these is not clinically useful in the evaluation of recurrent pregnancy loss. Prevention There is no preventive strategy available.

Therapy

There are usually two ways of dosing heparin: 1. Prophylactic anticoagulation typically implies low dosing (usually without monitoring, Table 26.4). If prophylactic adjusted-dose, this implies anti Xa level of 0.20.4 U/mI. 2. Therapeutic anticoagulation implies higher dosing (always adjusted dosing), meaning usually adjusted to anti Xa levels of 0.51.2 U/mi (Table 26.5).

Evidence 1. Compared with placebo or usual care, low-dose aspirin (ASA, acetylsalicylic acid) is not associated with any difference in outcome in pregnant women with APS. The summary relative risk (RR) for recurrent pregnancy loss is 1.05 (95% CI 0.66-l.68). 2. Compared with low dose ASA alone, unfractionated heparin and low-dose ASA in APS patients with recurr ent pregnancy loss are associated with significant reduction in pregnancy loss, with a summary RR of 0.48 (95% CI 0.330.68) for the three combined studies. 3. Compared with low-dose ASA alone or placebo, prednisone and low-dose ASA are not associated with a significant difference in pregnancy loss, with an RR of 0.85 (95% CI 0.53-l.36). However, there were significant higher rates of PTB in the prednisone groups in both tria ls and higher neonatal intensive care unit (NICU) admissions in one study. There were also lower birth weights in the prednisone group in one of the studies.

4. Compared with heparin and low-dose ASA, prednisone and low-dose ASA are associated with no difference in pregnancy loss rates, but again the prednisone group had a significantly higher rate of PTB. 5. In women already on heparin and ASA, the addition of intravenous immunoglobulin (IVIG) did not affect pregnancy loss rates in a very small.,trial, but was associ ated with a significantly higher PTB rate.3 This therapy is very expensive, and the only treatment shown to lower anticardiolipin levels. Actual therapy

APS with pregnancy loss or prior thrombosis: low-dose - ASA and prophylactic heparin.

Therapy is usually begun once fetal viability is established, but there is insufficient evidence regarding the best time of initiation of therapy. Low-dose ASA dose is usually about 75100mg daily. For propilylactic unfractionated heparin: 50007500 units first trimester; 7.500 l0.000 units second trimester, 10.000 units third trimester SQ q 12h. For prophylactic LMW heparin: enoxaparin (Lovenox) 30 40 mg SQ q 12h or dalteparin (Fragmin) 5000 u SQ ql2h (may adjust prophylaxis in high-risk cases to heparin [antiXa] level range 0.20.3).

APS with VTE during pregnancy: therapeutic anti- coagulation Therapeutic unfractionated heparin: doses need to be adjusted to keep aPTT 23 times normal. Therapeutic LMW heparin: enoxaparin 1 mg/kg ql2h, or dalteparin 200 units/kg ql2h. Discontinue ASA just before delivery. Must adjust therapeutic LMW heparin to heparin [antiXa] level 0.51.2. Consider switching from LMW heparin to unfractionated heparin at 36 weeks (or earlier if high risk for PTB).

APS with PTB secondary to early-onset FGR, other signs of placental insufficiency (see page 175, clinical criteria) or severe pre-eclampsia There are no treatment trials to assess any therapy.

Unfractionated heparin is thus the only therapy that has shown a statistically significant reduction in pregnancy loss. The optimal dose and the exact population(s) in which this therapy is most effective are difficult to assess precisely given the loose inclusion criteria and small numbers of the trials. It is associated with a 5% decrease in bone mass density (BMD).

Supplemental calcium (calcium gluconate/carbonate 1500 mg daily) and vitamin D, as well as weight-bearing exercise, should be encouraged. Idiosyncratic thrombocytopenia, known as heparin-induced thrombocytopenia (HIT), occurs in <5% of women on heparin therapy, is usually mild, and usually starts 315 days after initiation of therapy. There is no evidence to assess warfarin therapy for women with extreme thrombotic histories, including recurrent thromboses or cerebral thrombosis. (See also Chapter 26.)

Antepartum testing Early ultrasound is essential for accurate dating. Prenatal visits can be more frequent, approximately every 2 weeks after 24 weeks. Initiate heparin once viability is confirmed. Detailed ultrasound at about 1820 weeks and followu p ultrasounds about every 46 weeks for growth, fluid volume, and Doppler evaluation of the fetus. Fetal surveillance testing at 32 weeks. Daily fetal kick counts.

Preparations for delivery Delivery by EDC (estimated date of confinement). If on LMW heparin, consider switching to tmfi-actiona ted heparin at 36 weeks to allow regional anesthesia.

Delivery Send placenta (decreased placental weight, ischemich hypoxic changes infarctions, decidual and fetal thrombi, chronic villitis).

Anesthesia If on unfractionated heparin, regional anesthesia can be administered usually 68 hours after the dose, or at least when the aPTT is within normal limits. If on LMW heparin, regional anesthesia should be delayed until 24 hours after the last dose, since there is a risk of spinal hematoma if regional anesthesia is performed within 24 hours. That is why a woman on LMW heparin should be switched off LMW heparin on to unfractionated heparin weeks. before any chance- of labor or delivery (usually around 36 weeks if no other risk of PTB).

Postpartum/breastfeeding In women with APS based on recurrent embryonic loss at <10 weeks, the use of anticoagulation in the postpartum period has never been shown to be helpful. In women with APS based on fetal loss at 10 weeks and no thrombotic events, anticoagulation for 6 weeks is usually recommended in the USA2 (only 35 days in the UK). Women with APS based on prior thrombotic events should be switched to warfarin therapy. Warfarin therapy is safe in hreastfeed ing women. An international normalized ratio (INR) of 3.0 is desirable. Estrogen-containing oral contraceptives should be avoided, as they further increase the VTE risk. It is imperative that women with APS be followed closely by a medical or hematological specialist aftor pregnancy. About 50% of women with APS develop thromboses in the 310 years after delivery, and about 10% develop SLE.