The Antiphospholipid (Hughes) Syndrome
IntroductionThe Antiphospholipid Syndrome (APS) is a hypercoagulable disorder in which patients may develop vascular thrombosis and/or recurrent pregnancy loss. 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.
Clinical ManifestationsThrombosis, the main complication of APS, can affect venous and arterial vessels of all sizes; the consistent histopathological lesion is a bland thrombus without inflammation. The worldwide interest in this syndrome has led to its recognition in a wide variety of clinical states, leading to an increase in diagnosis. Indeed, it seems a fairly safe prediction that APS will overtake lupus in prevalence. A rough one-in-five rule seems to apply to the contribution of APS in various clinical conditions, i.e. one in five cases of recurrent miscarriage, one in five strokes in people under 45, one in five cases of deep vein thrombosis (DVT).
• Venous Thrombosis: Thrombosis of the deep veins of the lower extremities has been reported most frequently. Occasionally, the first episode follows pregnancy or the use of estrogen-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 and renal vein thromboses.
• Arterial 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 intracranial 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 (avascular necrosis and bone fractures).
• Pregnancy loss: 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 second and third trimester are associated with a high incidence of preeclampsia and intrauterine growth restriction, placental abruption and premature delivery. Histological examination of the placenta from these pregnancies often shows thromboses of the uteroplacental vasculature and placental infarction. aPL are present in 15-20% of apparently healthy women who have suffered recurrent pregnancy losses.
• Other features: Thrombocytopenia is common in patients with APS but is usually mild (platelet count 75-100,000). Some patients with Evans’ Syndrome (thrombocytopenia and haemolytic anemia) 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 with migraine. Valvular heart disease is a common, although often subclinical, association of the syndrome. Mitral valve thickening with associated regurgitation is the most common lesion. Livedo reticularis (a blotchy lacy pattern on the skin, most commonly seen on the knees, thighs and upper arms) is an important marker for APS. Some patients with Sneddon’s Syndrome (a triad of livedo reticularis, ischemic cerebrovascular disease and hypertension) have been found to be aPL positive. Skin vessel thrombosis can occasionally lead to ulceration, often in the lower leg. The link between high blood pressure, renal artery stenosis and APS has now been well established.
Mechanisms of thrombosisDespite 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.
Treatment• Management 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 ratio (INR) has 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 the risk is not higher than that observed in other thrombotic conditions warranting oral anticoagulation. Many APS patients have benefited from self-testing their own INR. Small commercial machines are now available, which give an immediate fingerprick INR reading – invaluable for those with busy lives, travellers, or for those patients who live far from their local anticoagulation clinic.
• Management of pregnancy in APS: 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 choice lies between aspirin, heparin or both. 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 foetal malformation. 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 gammaglobulin (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 foetal complications, including intrauterine growth restriction, pre-eclampsia and premature birth, hence, close monitoring including uterine artery Doppler scans and timely delivery may improve foetal outcome in these women.
• Management of patients with aPL without prior thrombosis: The controversy concerning whether or not prophylactic treatment is indicated for patients with aPL who have no prior history of thrombosis remains unresolved as there are no available data to identify which patients with aPL will thrombose. It is recommended that individuals with persistently positive aPL tests take low-dose aspirin (75 mg daily) along with the removal or reduction of other risk factors for thrombosis (i.e. smoking, obesity, high blood pressure, hypercholesterolemia and estrogen-containing oral contraceptive pills). Hydroxychloroquine could be safely prescribed as it has been shown to be protective against the development of thrombosis in aPL-positive lupus patients.
PrognosisGiven correct diagnosis and treatment, the outlook of APS patients is good. For those with serious events such as pulmonary embolism or stroke, lifelong anticoagulation treatment is needed. If treatment is managed carefully no further clotting episodes should occur.
APS has had a dramatic impact on pregnancy and is now regarded as a common treatable cause of recurrent miscarriage. Low-dose aspirin and heparin have significantly improved the pregnancy success rate (85-90%) in women with aPL.
Table 1 - Classification Criteria for APSClinical
1. Vascular Thrombosis: venous, arterial or small vessel
2. Pregnancy morbidity:
o 3 or more consecutive miscarriages (less than)10 weeks
o 1 or more foetal loss (greater than)10 weeks
o 1 or more premature births (less than)34 weeks due to severe pre-eclampsia or placental insufficiency
1. Anticardiolipin antibody: IgG and/or IgM (medium/high titre) on 2 or more occasions, 12 weeks or more apart.
2. Anti-ß2-Glycoprotein I antibody: IgG and/or IgM (medium/high titre) on 2 or more occasions, 12 weeks or more apart.
3. Lupus anticoagulant: positive on 2 or more occasions, 12 weeks or more apart
APS is present when one or more clinical and one or more laboratory criteria occur in the same patient
Dr Munther A Khamashta
Senior Lecturer/Consultant Physician
Director Lupus Research Unit
St Thomas’ Hospital
London SE1 7EH