Making the Difference
Reproduced from Issue 115 of Arthritis Today
Dr Munther Khamashta and his colleagues at the Lupus Research Unit at St Thomas' Hospital, explain how antiphospholipid syndrome is now a treatable condition.
For years patients with antiphospholipid syndrome (APS) went undiagnosed and untreated. Now, once the condition is diagnosed through a simple blood test, treatment can make an enormous difference.
Patients with APS have "sticky blood", which leads to an increased risk of thrombosis – clotting – in the veins and arteries. In pregnant women, the syndrome can also lead to frequent miscarriage. It is often associated with systemic lupus erythematosus (SLE).
In 1983 Dr Graham Hughes, the head of the Lupus Unit at St Thomas's, first identified the association of antiphospholipid antibodies (aPL) with an unusual combination of clinical features of vein and arterial thrombosis, miscarriage, and reduction in the number of platelets (thrombocytopenia) in the absence of classical SLE.
Thrombosis
Deep vein thrombosis (DVT) in the legs is the most frequently reported symptom. This may be a one off, or be recurrent. In some women, it happens soon after they start taking the oral contraceptive pill. The major concern in DVT patients is the risk of it spreading to the lungs (pulmonary embolism). Internal organs may also clot, such as the kidney, liver, brain and eye.
Major artery thrombosis is less common than in the veins. However, thrombosis in the arteries has more severe consequences, particularly in small arteries in the brain, when it can lead to stroke. Other arterial thrombosis may also occur, e.g. eye, renal, coronary and peripheral arteries.
Recurrent miscarriage is now treatable
Tne of the gains from the recognition of APS Syndrome is that it is a significant cause of recurrent miscarriage. Thankfully, this is now treatable. The simple theory as to the cause is that the "sticky blood" is unable to reach the smallest blood vessels in the placenta.
Pregnancy complicated by APS requires expert care and a multidisciplinary team approach. In our pregnancy clinic, patients with APS undergo assessment and counselling before they conceive. Close monitoring of pregnancy is essential.
For women with recurrent miscarriages, but without a history of clotting, the traditional treatment is low dose aspirin. Heparin is also increasingly being used in these patients especially if they had previous miscarriages during the second or third trimester, or other pregnancy complications such as pre-eclampsia. For those women with previous thrombosis we use aspirin together with subcutaneous heparin injections. Heparin is the anticoagulant treatment of choice during pregnancy, as warfarin is toxic to the developing foetus. The success rate in APS pregnancy has risen from 20% to over 70%.
Other symptoms
As already mentioned, the most dramatic and serious neurological symptom is of course, is a stroke, but also includes seizures, movement disorders (including chorea), memory loss, visual disturbances, spinal cord problems and migraine. Our most recent experience on a group of 345 SLE patients showed that aPL were significantly more frequent in patients with chronic headache than in those without. Interestingly, in some of our patients with severe and chronic headache resistant to conventional treatment, it often reduced or went completely when treatment with heparin or warfarin was started to treat thrombosis.
Some patients with APS can exhibit symptoms that very often mimic multiple sclerosis (MS). In our experience, a careful medical history, a previous history of thrombosis and/or recurrent miscarriage, an abnormal brain scan, and response to anticoagulant therapy all contribute to reaching a correct diagnosis. We believe that testing for aPL should become routine in patients with "atypical" MS. Although the threat of the development of a stroke is the biggest fear, one wonders how many individuals with more subtle forms of brain involvement are either being misdiagnosed, or not being diagnosed at all.
Heart symptoms are frequent in APS patients. There are two areas of the heart which can be affected; the heart valves and the coronary arteries. Early myocardial infarction (heart attack) has been documented both in patients with APS associated with SLE and in the primary APS. Valve involvement is seen in up to 35% of patients, mitral valve involvement being the most frequent, and can be confirmed by echocardiography, which is now a part of the routine screen in our APS clinic.
Renal disease, in particular thrombosis of the kidney artery with restricted blood supply to the kidney and raised blood pressure is also a risk in patients with APS. Renal vein thrombosis may also occur.
In a small percent of patients, the platelet numbers are affected and, rarely, platelet counts may fall to dangerously low levels. Thus, patients who have been diagnosed as having low platelet counts (thrombocytopenia) should also be checked for the syndrome.
Blotchy skin (livedo reticularis) is frequent, and some patients develop a purplish vein coloration on the back of the wrists and others on the knees. Skin ulcers are also a common complication in APS. They normally appear in the legs although they can be widespread.
Widespread clots involving vital organs is a life-threatening condition fortunately rare in APS patients. This variant of the syndrome, is precipitated by infections, surgical procedures, and anticoagulation treatment withdrawal. The patient becomes extremely ill and requires intensive care treatment.
Treatment
APS patients with a history of clots are at risk of this happening again, and clots can be prevented by a long-term oral anticoagulation treatment, warfarin, which thins the blood. In APS patients we try to keep the blood two to four times thinner. Patients on warfarin treatment undergo regular blood testing. The most serious side effect during treatment is internal bleeding, therefore the optimal dose of warfarin needs to be balanced according to the therapeutic effect required and the risk of bleeding for each individual.
Patients with positivity for aPL but without history of thrombosis generally do well with low dose aspirin (75–100 mgs) daily in order to reduce platelet stickiness and prevent clots. Aspirin is the safest form of prophylaxis, or prevention, of thrombosis, the most common side effect being limited to indigestion and the most serious, but rare, to allergic reactions. Though aspirin is the logical first line treatment, aspirin alone is often not enough and some aPL positive patients develop thrombosis despite treatment.
We wondered whether a possible therapeutic alternative to aspirin – in selected patients – might be a low dose of warfarin. In order to provide evidence we have designed a five year study which is funded by arc. An international collaborative clinical trial comparing aspirin alone versus aspirin plus low dosage of warfarin has been started.
Antiphospholipid antibody testing
There are two main types of aPL tests that are used for the diagnosis: the first is the anticardiolipin antibody (aCL), which is an immunological test, and the second one is the lupus anticoagulant (LA), which is a coagulation-based test. Although they measure broadly the same thing, a sizeable number of cases (around 20%) one or other test may prove negative. In other words, one test alone could miss the diagnosis. These tests are available in most major hospitals throughout the world, and clinicians now recognise that these simple tests can make a great difference to treating patients with this condition.
