A 41-year-old man with abdominal pain
2. What further investigations are indicated before starting treatment?
- No further investigations required
- Repeat testing for phospholipid antibodies in 12 weeks
- Test for antinuclear antibodies
Antiphospholipid antibodies may appear transiently in certain infections, such as syphilis, Lyme disease, Epstein-Barr virus, cytomegalovirus, hepatitis C, and human immunodeficiency virus. Therefore, the presence of antiphospholipid antibodies must be confirmed over time, with two positive results at least 12 weeks apart.2
When repeated 12 weeks later, our patient’s IgG anticardiolipin antibody level was 14 GPL units, and the IgM anticardiolipin antibody level was 30 MPL units; the dRVVT was 55 seconds, and the dRVVT ratio was 1.8. These results, along with a history of recurrent arterial thrombosis, confirmed antiphospholipid syndrome.
The 2009 update of the International Society of Thrombosis and Haemostasis guidelines recommend two tests, the dRVVT and the aPTT, since no single test is 100% sensitive for lupus anticoagulant.3 The dRVVT has a high specificity for lupus anticoagulant in patients at high risk of thrombosis.
A SYNDROME WITH A WIDE RANGE OF EFFECTS AND COMPLICATIONS
Antiphospholipid syndrome is a systemic autoimmune disease that manifests as arterial and venous thrombosis and as obstetric complications. Thrombosis tends to be recurrent and may involve any site. For example, it can cause blurred vision in one or both eyes; amaurosis fugax; visual field defects; central or branch retinal artery or vein occlusion; deep vein thrombosis; pulmonary embolism; myocardial infarction; transient ischemic attack and stroke; cerebral vein thrombosis; and portal, renal, and mesenteric infarction involving veins or arteries.4 Pulmonary capillaritis may cause diffuse alveolar hemorrhage. Livedo reticularis, digital gangrene, cutaneous necrosis, splinter hemorrhages, chorea, and transverse myelopathy may also occur.
Obstetric complications of antiphospholipid syndrome include recurrent miscarriage and pregnancy loss at or after 10 weeks of gestation, eclampsia, preeclampsia, and placental insufficiency.5 The syndrome also has a potentially lethal variant characterized by multiorgan thrombosis affecting mainly small vessels.
The diagnosis of antiphospholipid syndrome requires relevant clinical features and symptoms and the presence of at least one of the antiphospholipid antibodies. Because the rate of false-positive tests for antiphospholipid antibodies ranges from 3% to 20% in the general population, asymptomatic patients should not be tested.6
Antiphospholipid syndrome may occur in the setting of other autoimmune diseases, most commonly systemic lupus erythematosus, when it is termed “secondary” antiphospholipid syndrome. Although only 40% of patients with lupus have antiphospholipid antibodies and less than 40% will have a thrombotic event, thrombotic antiphospholipid syndrome is a major adverse prognostic factor in these patients.7,8 Therefore, it is prudent to consider systemic lupus erythematosus and to do appropriate tests if the patient has other features suggestive of lupus, such as renal, skin, or musculoskeletal lesions.
In our patient, antinuclear antibody testing was positive, with a titer of 1:320, and showed a finely speckled staining pattern. Tests for antibodies to Sjögren syndrome A and B antigens were negative. The complement C3 level was 1.28 g/L (reference range 0.74–1.85) and the C4 level was 0.24 g/L (0.16–0.44). Although the speckled staining pattern can be seen in lupus, it is more common in Sjögren syndrome, mixed connective tissue disease, scleroderma, and CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia).9 Moreover, normal levels of complement C3 and C4, in the absence of clinical features, make lupus unlikely. Similarly, our patient had no clinical features of other connective tissue disorders. Therefore, he had primary antiphospholipid syndrome.
3. How should this patient be managed?
- Antiplatelet therapy
- Warfarin to maintain an INR between 2.0 and 3.0
- Warfarin to maintain an INR above 3.0
The risk of recurrent thrombosis is high in patients who test positive for lupus anticoagulant, and the risk is highest in patients who are also positive for anticardiolipin and anti-beta-2 GP1 antibodies: the incidence of thrombosis is 12.2% at 1 year, 26.1% at 5 years, 44.2% at 10 years.10
Since our patient is positive for lupus anticoagulant (prolonged aPTT and elevated dRVVT, both indicating lupus anticoagulant positivity) and for anticardiolipin antibodies (anti-beta-2 GP1 not tested), his risk of recurrent thrombosis is high, and he requires lifelong anticoagulation therapy.
The intensity of anticoagulation in different subgroups of patients is controversial. Based on retrospective trials, indefinite anticoagulation at an INR of 2.0 to 3.0 has been suggested for patients with antiphospholipid syndrome presenting with venous thrombosis, and more intense anticoagulation with an INR above 3.0 in patients with recurrent or arterial thrombosis.11 The combination of warfarin with an INR between 2.0 and 3.0 and aspirin 100 mg daily has also been proposed for patients with arterial thrombosis.12
Modifiable risk factors such as smoking, obesity, and use of estrogens should be addressed in all patients with antiphospholipid syndrome.
In pregnant women with complications such as preeclampsia, low-dose aspirin can be used, and in women with a history of miscarriage, the combination of low-dose aspirin and heparin is recommended throughout the prenatal period.4
In patients who have recurrent thrombosis despite adequate anticoagulation, an expert committee12 has proposed that alternative regimens could include long-term low-molecular-weight heparin instead of warfarin, the combination of warfarin and aspirin, or warfarin and hydroxychloroquine. Adding a statin can also be considered.
Treatment of catastrophic antiphospholipid syndrome is based on expert opinion. A combination of anticoagulation, corticosteroids, plasma exchange, intravenous immunoglobulins, and rituximab has been tried, but the mortality rate remains high.13
OUR PATIENT'S COURSE
Our patient was started on warfarin, with a target INR above 3.0, and was doing well at 6 months of follow-up.
