LUPUS: A GP Guide to Diagnosis
The antiphospholipid syndrome (APS) is a hypercoagulable disorder in which patients may develop both venous and arterial occlusions. Its serological marker is the presence of antiphospholipid antibodies (aPL) (Table 1). Although initially described as a complication of lupus, it is now clear that the syndrome can occur without any other evidence of a connective tissue disease - the so-called Primary APS.
Thrombosis, the main complication of APS, can affect venous and arterial vessels of all sizes; the consistent histopathological lesion is a bland thrombus without inflammation.
Thrombosis of the deep veins of the lower extremities has been reported most frequently. Occasionally, the first episode follows pregnancy or the use of oestrogen-containing oral contraceptive pills. Thrombosis often recurs and may be accompanied by pulmonary embolism. Some patients with aPL also have pulmonary hypertension, perhaps caused by recurrent pulmonary emboli. More major venous thrombosis may involve the thoracic outlet veins or the inferior vena cava. Serious organ involvement includes hepatic thrombosis (APS is the second most common cause of Budd-Chiari syndrome), adrenal thrombosis leading to Addison's disease, retinal vein thrombosis and renal vein thrombosis.
Distinct from most other thrombophilic disorders, arterial thrombosis and accelerated arterial disease are striking manifestations of APS and are prognostically critical. Occlusions of the intrancranial arteries have been reported most frequently, with the majority of patients presenting with strokes and transient ischemic attacks. Magnetic resonance imaging scans show changes that vary from single lesions to multiple widely-scattered infarcts. Cognitive and psychiatric features have been prominent in the presentation of some patients with APS. Large peripheral artery occlusions causing limb claudication, ischemia and gangrene have also been reported. The aorta may be involved, as well as vascular territories that include the liver, the kidney, the heart, the gut, the eye, the skin and even the skeletal system.
Recurrent spontaneous pregnancy loss is one of the most consistent complications of APS. Loss can occur at any stage of pregnancy, although aPL-related miscarriages are strikingly frequent during the second and third trimester. APS pregnancies, which proceed into the third trimester, are associated with a high incidence of pre-eclampsia and intrauterine growth restriction, placental abruption and pre-maturity. Histological examination of the placenta from these pregnancies often shows thromboses of the uteroplacental vasculature and placental infarction. aPL are present in 10-15% of apparently healthy women who have suffered recurrent pregnancy losses.
Thrombocytopenia is common in patients with APS but is usually mild (platelet count 75-150 x 109L). Some patients with Evans' syndrome (thrombocytopenia and haemolytic anaemia) have been found to be aPL positive. Epilepsy is significantly associated with moderate to high titres of aPL in patients with lupus and has been described in patients with Primary APS. It is possible that seizures in APS are the expression of ischemic events from vascular occlusions of small cerebral vessels. A similar mechanism may explain the association of APS and migraine. Transverse myelitis and chorea are other recognised neurological features of APS. Valvular heart disease is a common, although often subclinical, association of the syndrome. Mitral valve thickening with associated regurgitation is the most common lesion. Some patients with Sneddon's syndrome (a triad of livedo reticularis, ischemic cerebrovascular disease and hypertension) have been found to be aPL positive.
Despite the strong association between aPL and thrombosis, the mechanisms remain to be defined. The antibodies are directed against phospholipid-protein complexes and may have a direct effect on certain key membranes (e.g. platelets, endothelial cells). The antibodies may also affect the clotting mechanism itself or, more directly, key "clotting" proteins (e.g. thrombomodulin, Protein C, Protein S). Several animal models have been established to study the syndrome and they are providing further insights into the mechanisms of thrombosis in APS.
Clinical experience suggests that patients with high titres of aPL and previous major thromboses require long-term, possibly life-long, anticoagulation; in these patients international normalised ratios (INR) have to be kept around 3.0. Steroids and immunosuppressive drugs to reduce antibody titres have not provided long-term benefit. Bleeding complications may occur but their risk is not higher than that observed in other thrombotic conditions warranting oral anticoagulation.
The management of pregnancy in women known to have APS is the subject of much debate and, as yet, there have been very few randomised controlled trials. Anticoagulation in one form or another is the preferred treatment rather than steroids (once widely recommended). The current choices lie between aspirin, heparin or both. At St. Thomas' Hospital Lupus Unit experience with low-dose aspirin as the only treatment in aPL-positive women with recurrent pregnancy loss but without a history of thrombembolism has been good, with 70% having successful pregnancies. Ideally, pregnant women with APS and a previous thrombosis should stop warfarin as soon as possible after a positive pregnancy test to prevent the development of warfarin-related fetal malformations. Subcutaneous, self-administered heparins are the thromboprophylaxis of choice with low molecular weight heparins being the preferred drugs. For patients who continue to have pregnancy losses despite heparin and low-dose aspirin treatment, intravenous gamma globulin (IVIG) may be an option. IVIG is, however, extremely expensive and definitive proof of its efficacy is needed before endorsing its wider use.
Most authorities agree that one of the main reasons for the improving outcome of APS pregnancies is the closer obstetric surveillance. Viable APS pregnancies have a high incidence of obstetric and fetal complications, including intrauterine growth restriction, pre-maturity and pre-eclampsia, hence, close monitoring including uterine artery doppler scans and timely delivery may improve fetal outcome in these women.
Table 1 - Classification Criteria for APS Clinical
Laboratory
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Dr. Munther A. Khamashta
Senior Lecturer/Consultant Physician
Lupus Unit
St. Thomas' Hospital
London, SE1 7EH