The Antiphospholipid (Hughes) Syndrome
IntroductionA series of papers published in 1983, described a clinical syndrome characterised by a tendency to thrombosis (both venous and arterial), recurrent miscarriage, and prominent neurological problems. Serologically the syndrome was characterised by the presence of antiphospholipid antibodies (aPL). In normal practice aPL are measured in three major ways. These include anticardiolipin antibodies (ACA), antibeta 2 glycoprotein-1 (ab2GP1) and lupus anticoagulant (LA).
In the ensuing years the antiphospholipid antibody syndrome (APS) has become recognised as an important general medical condition touching on many specialties.
“One in 5”
Antiphospholipid antibodies (aPL) have been reported and seem to occur in around:
1 in 5 DVT’s
1 in 5 cases of recurrent miscarriage
1 in 5 cases of stroke in women under 45
1 in 5 cases of idiopathic teenage epilepsy
1 in 5 cases of lupus
The Clinical PictureA formal diagnosis of APS must include both clinical features of thrombosis and the presence of a defined antiphospholipid antibody or positive lupus anticoagulant on laboratory testing. The current diagnostic criteria are detailed below (Ref: Bustamante J. et al Antiphospholipid Syndrome (Antiphospholipid Antibody Syndrome, APS, APLS) 2019 Nov 05, [PubMed])
The presence of either vascular or pregnancy morbidity as below
1. One or more episodes of venous, arterial or small vessel thrombosis with unequivocal or histological evidence of thrombosis
2. Pregnancy morbidity as defined by one or more of the following:
• Unexplained foetal death at >10 weeks gestation of a normal foetus
• 3 or more pregnancy losses <10 weeks gestation of no alternative identifiable cause
• Premature birth before 34 weeks gestation due to pre-eclampsia, Eclampsia, or placental insufficiency.
The presence of aPL on 2 or more occasions 12 weeks apart and not more than 5 years prior to the development of clinical features as defined by one or more of the following:
• IgG and/or IgM anticardiolipin antibodies in moderate or high titre
• Antibodies to Beta2-Glycoprotein I of IgG or IgM isotype
• Lupus anticoagulant (LA) activity Patients frequently have symptoms that are not captured by the diagnostic criteria.
Nervous SystemThe most severe neurological sequel in APS is thrombotic stroke which can be the presenting complaint in young patients. Other features are migraine headaches, memory loss, balance problems, movement disorders and seizures.
The spinal cord can be affected, in some cases mimicking multiple sclerosis, due to ischaemic damage secondary to thrombosis of vertebral vessels. This can result in ataxia, and sudden onset transverse myelitis with rapidly progression of paralysis.
CardiovascularCoronary artery disease and acute cardiac ischaemia secondary to coronary thrombosis is a recognised complication of APS. Young patients with other cardiovascular risk factors such as smoking and hypercholesterolaemia are particularly at risk of developing premature coronary artery disease and myocardial ischaemia and risk factors should be targeted aggressively in this group of patients.
Valve disease is a recognised late complication of APS. Small vegetations can develop on the heart valve, consisting of fibrous tissue and thrombotic debris. These vegetations are particularly common on the mitral valve where they can cause mitral regurgitation and increase the risk of infective endocarditis. Some patients will eventually require valve surgery.
Renal TractChronic subclinical thrombosis can occur in the small renal vessels and glomeruli which, over time, leads to a decline in renal function as glomeruli become sclerosed. Renal artery and renal vein thrombosis are reported, in which case a sudden deterioration of renal function and pain is frequently present. Renal artery stenosis can occur as a late complication with consequent effects on blood pressure control.
HaematologicalThe most common problem detected on the blood film is thrombocytopenia. This is usually mild and bleeding is not a problem but, in some cases, can become severe and then treatment is complicated and usually managed in conjunction with haematologists and rheumatologists.
PregnancyAPS is now recognised as the commonest, treatable cause of recurrent miscarriage. Most pregnancy losses are in the first trimester but some occur later in the pregnancy and features of placental insufficiency can occur at any time from the second trimester onwards. Successful pregnancy outcomes are imprving in women with APS. However, treatment with anticoagulants (heparin) and close monitoring of the pregnancy, with careful timing of delivery, is required by obstetric teams experienced in managing such pregnancies for the best outcomes. Women should be counselled regarding pregnancy prior to conceiving.
Links with other conditionsAPS can occur in isolation (primary APS) where there is no evidence of another autoimmune disease present. Many cases, however, will occur in combination with another autoimmune disease (secondary APS). The most common condition that secondary APS occurs in is lupus. All patients with lupus should be screened for the presence of aPL antibodies. Other autoimmune conditions in which APS can be found include Sjögren's Syndrome, rheumatoid arthritis and autoimmune thyroid disease.
TreatmentCurrent treatment consists of anti platelet agents or anticoagulants.
1. Antiplatelet agents
• First choice for milder cases, for example, those with frequent headaches but no obvious thrombosis. Newer antiplatelet agents such as ADP receptor blockers (e.g. clopidogrel ) and Glycoprotein inhibitors (e.g. abciximab) can be used but evidence for their use is limited in APS.
• Heparin (low molecular weight/L.M.W.) has 2 main uses in APS. Firstly, as conventional therapy in a new thrombosis, or around the time of surgery. Secondly, in pregnancy where a combination of aspirin and L.M.W. heparin has dramatically improved the outcome in APS patients suffering recurrent pregnancy loss.
• Warfarin remains the treatment of choice for severe cases, partly because the dosage and degree of anticoagulation can be controlled. Patients with recurrent thrombotic episodes despite adequate anticoagulation with an INR 2-3 will need their dose adjusted to push the INR range to the 2.5-4 range.
• New oral anticoagulants are now being used in APS. They have the advantage over warfarin in that they have stable dosing and do not require regular blood test monitoring. However, there are concerns that they may not be effective leading to a risk of further thrombosis, published trial comparisons with warfarin remain inconclusive as to their effectiveness in APS over warfarin.
Hydroxychloroquine has been shown to have a mild anti-thrombotic effect in APS and SLE patients. It is not effective enough on its own for treatment of APS but will frequently be added to patients’ treatment for a synergistic effect.
ConclusionAPS is a relatively common, major illness, with an impact not only in rheumatology, but throughout the whole of medicine, surgery and obstetrics.
Prof Graham RV Hughes
Hon Life President LUPUS UK
The London Lupus Centre
London Bridge Hospital
27-29 Tooley Street
London, SE1 2PR
Dr Nicola Erb
Dudley Group NHS Foundation Trust
Department of Rheumatology
Russells Hall Hospital
West Midlands, DY1 2HQ