Graham Hughes1 and Shirish Sangle2
(1)
The London Lupus Centre, London Bridge Hospital, London, UK
(2)
Louise Coote Lupus Unit, St Thomas’ Hospital, London, UK
Abstract
Put at its simplest, there are three treatments for APS, aspirin, heparin and warfarin. This somewhat truncated overview, however, hides the fact that treatment can be very effective, despite the limited therapeutic armoury.
Put at its simplest, there are three treatments for APS, aspirin, heparin and warfarin. This somewhat truncated overview, however, hides the fact that treatment can be very effective, despite the limited therapeutic armoury.
21.1 Aspirin
Because of its effects in reducing platelet stickiness, low-dose aspirin (75–100 mg daily) is extremely useful in APS. Although evidence-based data have proved rather elusive, aspirin is the drug of choice for milder cases of APS, for example, those without previous major thrombosis. It is also used as prophylaxis for aPL-positive individuals who have not had major medical problems – though studies are still ongoing. Perhaps the best data on aspirin use in aPL-positive persons have come from pregnancy studies, where low-dose aspirin in aPL-positive pregnancies has contributed to the dramatic improvement in pregnancy success rates in these women.
Clinically, the efficacy of “junior” aspirin can often be seen in the improvement in severity and frequency of migraines. However, not all patients respond. Possibly this reflects the possible different mechanisms in APS, aspirin working solely on platelets.
A number of patients (such as asthmatics who may not be able to tolerate aspirin) respond equally well to Plavix (clopidogrel) 75 mg daily.
While there is a big literature comparing aspirin and clopidogrel in the field of cardiology, no similar comparative trials have yet been completed in APS.
Finally, dosage. Occasionally, some patients who achieve partial success on 75 mg aspirin daily appear to improve further at a dose of 150 mg daily – though these are a minority.
21.2 Heparin
Although some countries cling to old-fashioned heparin, for most centres, this has been replaced by low molecular weight (LMW) heparins (e.g., enoxaparin or dalteparin) (Fig. 21.1).
Figure 21.1
Low-molecular-weight heparin pre-filled syringe
LMW heparins are well tolerated, easy to self-administer and very safe. The well-known problems of “old” heparin (e.g., heparin-induced thrombocytopenia and osteoporosis) appear to be very rare with LMW heparin.
Heparin is widely used as first line therapy after thrombosis but has many other uses, e.g., peri-operatively or during intravenous infusions to keep the line clear.
In Hughes Syndrome, LMW heparin has found a number of other uses, including pregnancy, IVF and occasionally in diagnosis and management of some of the neurological features of APS.
In pregnancy, most specialist units use a combination of aspirin and LMW heparin in APS women with previous thrombosis and recurrent pregnancy loss, though there is still debate about best treatment.
Although heparin requires self-injection daily for several months in these pregnancies, it is surprisingly well tolerated and side effects are rare. It is no longer considered necessary to measure factor X-a levels routinely.
In neurology, we have found a short course of heparin useful as a diagnostic aid. It is not unusual for a patient with Hughes Syndrome on, say, aspirin 75 mg daily, to suffer increasingly severe hemiplegic migraines. In such a patient, with no previous history of thrombosis, warfarin treatment would seem a step too far. We have found that a standardised course of heparin – for example, Fragmin (dalteparin) 10,000 iu. daily subcutaneous for 3–4 weeks, often gives a clear idea as to whether the symptoms can be relieved by anticoagulation. While obviously a rather “soft” therapeutic trial, we have found it to be invaluable in the management of some patients.
21.3 Warfarin
For those patients with major thrombotic histories or severe neurological features such as stroke, warfarin treatment is vital.
Sadly, warfarin comes up against two widely held opinions – firstly that warfarin (“rat poison”) is toxic (fortunately, apart from its effects as an anticoagulant, side effects are rare) and secondly in stroke. There is often still more of a fear of bleeding than of clotting – the danger in Hughes Syndrome is one of clotting.
Another problem concerns INR levels. Many patients with Hughes Syndrome require a higher INR (thinner blood) than the average anticoagulant clinic patient.
This is often especially the case with some of the neurological problems, where INR levels of 3.5–4 may be required. It is not uncommon for patients with Hughes Syndrome to “know” their INR, the headaches, dizziness and memory difficulties returning, for example, when the INR falls below, say, 3.5.
Of course warfarin control can be notoriously wayward. Patients come to clinic, for example, with a label of “unresponsive to warfarin” - in many cases a glance at the INR results shows the INR often not hitting the three level.
For this, and other reasons, it is my practice to encourage INR self-testing where possible – usually in collaboration with the anticoagulant clinic.
There are a number of self-testing kits available and most patients quickly learn the technique. A return of headaches, or dizziness, for example, quickly leading to a simple finger prick test and fine tuning, if need be, of the warfarin dose.
For many APS patients, INR self-testing has proved a liberating experience, allowing, for example, travel to other countries without fear.
21.4 Newer Anticoagulants
For some years, there has been a hope of newer anticoagulants, which hopefully don’t require injection, or INR testing. Some have fallen by the wayside in early trials, but one or two (e.g., debigatran – Pradaxa) are very promising and will hopefully prove of value in some cases of APS.
21.5 Steroids
Steroids are not indicated for thrombosis problems. However, they are still one of the first choices for the treatment of thrombocytopenia. They are also a part of the treatment of lupus, including those lupus patients with aPL-associated problems.
21.6 Immunosuppressives
Because Hughes Syndrome is an “auto-immune” condition, it seemed logical to attempt to address the problem of an overactive immune system.
Unfortunately, our early attempts at immunosuppressives – usually with azathioprine and cyclophosphamide – were disappointing and seemed to have little impact on the disease.
More recently, newer “selective” immunosuppressants, such as the anti-B cell agents rituximab and belimumab, have proved very promising in a number of autoimmune conditions such as lupus, and anecdotally, and in small numbers, positive reports in Hughes Syndrome are appearing. Early days!