Hughes syndrome antiphospholipid syndrome

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REVIEW ARTICLE

Year : 2018 | Volume : 11 | Issue : 4 | Page : 169-174

Hughes syndrome antiphospholipid syndrome

Graham Robert Vivian Hughes

The London Lupus Centre, London Bridge Hospital, London, England, UK

Date of Web Publication9-Nov-2018

Correspondence Address:

Prof. Graham Robert Vivian Hughes

The London Lupus Centre Ltd, 1st Floor, St. Olaf House London Bridge Hospital, 27 Tooley Street, London, SE1 2PR, England

UK

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/HMJ.HMJ_83_18

Abstract

Hughes Syndrome is now recognised world-wide as a common, major illness, impacting on specialties including neurology, cardiology and surgery. It is the commonest, treatable cause of recurrent miscarriage, and has had a profound impact on the practice of obstetrics.

How to cite this article:

Hughes GR. Hughes syndrome antiphospholipid syndrome. Hamdan Med J 2018;11:169-74

Available from: hamdanjournal.org/text.asp?...

Introduction

The antiphospholipid syndrome (APS) (Hughes syndrome) was described in 1983. In the following 35 years, the illness has become recognised worldwide – possibly for three main reasons:

It is readily diagnosed

Treatment – usually with anti-clotting agents, results in improvement – often dramatic

The syndrome impacts on all branches of medicine. Furthermore, the APS is common. Published studies have come up with a roughly 1 in 5 incidence, for example:

1 in 5 cases of recurrent miscarriage

1 in 5 cases of young (under 45) stroke

1 in 5 deep-vein thrombosis (DVTs)

1 in 5 idiopathic teenage epilepsy

1 in 5 cases of angina in women under 45

1 in 5 cases of lupus.

In addition, APS is strongly associated with migraine, as well as being a preventable cause of stillbirth and a differential diagnosis of some cases of multiple sclerosis.

Figures for the true prevalence are not yet available, but clearly the condition is being reported and treated globally.

The recognition that in some cases the tests remain negative (‘seronegative APS’) has raised an intriguing thought – how many APS patients are attending migraine clinics, MS, cardiology and rheumatology clinics with classical diagnostic features, yet negative tests, not yet treated.

History

In 1983, we published three papers describing the clinical features of a syndrome, as well as a serological test for ‘anti-cardiolipin antibodies.[1],[2],[3]’ I presented our findings to the British Rheumatology Society (The Heberden Society) in 1982 and to the British Dermatology Society in 1983 – published a year later in 1984.[4] Extracts from that paper are printed here:

‘Over the past 13 years at the Hammersmith Hospital I have seen a number of patients who appear to me to have a distinct syndrome or set of features. These have been referred to in previous Hammersmith meetings and publications, but this lecture gives me the opportunity to discuss this constellation of features in detail and to suggest certain pathogenic mechanisms’.

‘Although many of these patients fall under the general heading of lupus, or lupus-like disease, I believe that the group is sufficiently homogenous, and in some ways (such as the frequently negative ANA serology), sufficiently different from typical SLE to warrant separate consideration’.

‘The manifestations of this syndrome are thromboses (often multiple) and frequently spontaneous abortions (often multiple), neurological disease, thrombocytopenia, and livedo reticularis. The livedo is often most florid on the knees. This may or may not be associated with mild to moderate Raynaud's phenomenon’.

‘These patients’ blood pressure often fluctuate, apparently correlating with the severity of the livedo, suggesting a possible reno-vasulcar aetiology. However, this group of patients rarely has primary renal disease’.

‘The cerebral features are prominent and of 3 varieties:

Headaches – often migrainous and intractable Epilepsy (or abnormal EEGs)– often going back to early teenage. Fortunately severe or difficult to control epilepsy is infrequent. Some patients have chorea’.

‘Cerebrovascular accidents – sometimes transient and seemingly attributable to migraine, but frequently progressive. It is this aspect of the syndrome which I believe to be particularly significant. The patients may develop transient cerebral ischaemic attacks or visual field defects, or more significantly, progressive cerebral ischaemia’.

‘Two other features of the syndrome are a tendency to multiple spontaneous abortions and peripheral thrombosis, often with multiple leg and arm vein thrombosis. We have also seen Budd-Chiari syndrome and renal vein thrombosis in some of these patients. We have, of course, tended to group these patients under the diagnostic umbrella of systemic lupus, although an alternative label of “primary” Sjogren's syndrome covers other patients’.

‘To my mind, however, the most striking and often most serious feature of the disease is the tendency to thrombosis, particularly cerebral thrombosis. So prominent has this feature been that we have some patients in their 30s and 40s who had been diagnosed with primary cerebral vascular disease – or when the labile hypertension has been observed – as hypertensive cerebral vascular disease’.

‘The finding that many of these patients have high titres of circulating anti-cardiolipin antibodies leads us to believe that a new line of investigation may be possible in such patients’.

The background to the discovery came from our work in lupus – particularly cerebral lupus.[5],[6] In 1971, I set up the UK's first specific lupus clinic, the number of cases increasing year on year.

Over the years, we saw a number of cases whose features were broadly similar, but who did not fulfil the American College of Rheumatology classification criteria for lupus. Particularly interesting was a group resembling ‘lupoid sclerosis’ – a condition with overlapping lupus and MS features.

Together with my visiting fellows, notably Helen Englert, Genevieve Devue, May Ling Boey and Bernie Colaco, later, Charles Mackworth-Young and Ron Asherson, we began to collect and carefully document these cases. In the laboratory, led by Dr Aziz Gharavi and Nigel Harris, we worked on the development of sensitive assays for anti-cardiolipin (and, later other antiphospholipid antibodies (aPL).

In 1984, we held our first ‘International Antiphospholipid Antibody (aPL)’ workshop – a meeting which has become a regular event. At the 14th such meeting, held in Rio de Janeiro, I was invited to give the opening lecture, reviewing progress in the syndrome.[7]

In 1985, we opened the lupus clinic in St Thomas’ Hospital, where I was fortunate to have a series of outstanding research fellows, including Angela Tincani, Robert Roubey, Guillermo Ruiz-Irastorza and Ricard Cervera, and of course, Dr Munther Khamashta who become internationally recognised for his work in APS/Hughes syndrome, and who succeeded me as head of St Thomas’ Lupus Centre.

Clinical Features

Clotting

Spontaneous thrombosis can occur anywhere in the untreated patient. Critically, the clotting can occur in arteries as well as veins. In many patients, there is an obvious precipitating factor such as surgery, or immobilisation, or the oral contraceptive pill.

Who is affected?

Like many other auto-immune conditions, females outnumber males, and all age groups can be affected. There is often a positive family history of auto-immune conditions such as thyroid, multiple sclerosis, lupus or Sjogren's syndrome.

Pregnancy

Multiple pregnancy losses are one of the hallmarks of Hughes syndrome, some patients suffering 10, 12 or even 14 miscarriages. In other patients, late pregnancy loss – stillbirth – is seen. Another pregnancy complication of Hughes syndrome is IUGR (intrauterine growth retardation).

The cause of these pregnancy complications is thought to be ‘sludging’ of the blood supply to the placenta, though other mechanisms are also possible. Whatever the mechanism, the simple treatment with aspirin and/or heparin has raised the success rate in APS pregnancies from under 20% to over 90%.[8]

Nervous System

Stroke

One of the most feared complications of Hughes syndrome is stroke. Any age can be affected – one of my patients was 2 years old. There is often a preceding history of transient ischaemic attacks. Brain magnetic resonance imaging (MRI) may show numerous micro-infarcts (often in the past these were wrongly diagnosed as ‘vasculitis’).

A number of studies have shown that the presence of aPL is an important risk for stroke. One of the most striking reports came from Rome, where 1 in 5 young (under 45) strokes were aPL positive.[9]

Migraine

One of the most common complaints in Hughes syndrome is migraine – often with a history going back to the patient's teens.[10] Surprisingly, the true proportion of migraine sufferers with positive aPL is not known. However, the link is strong. One of the most dramatic observations in Hughes syndrome is the improvement, or even disappearance, of migraine when anti-platelet or anti-coagulant treatment is started.[11] We have suggested that APS may be an important link between migraine and stroke.[12]

Memory loss

Arguably the most common feature of Hughes Syndrome is memory loss, often mild, but sometimes severe enough to raise concerns over possible Alzheimer's. Like migraine, memory can be improved measurably when treatment – for example with heparin or warfarin – is started.[11]

Epilepsy

In recent years, epilepsy – in all its forms – from seizures to temporal lobe features, is becoming better recognised as a feature of Hughes syndrome. For example, one study of idiopathic teenage epilepsy found that 1 in 5 were aPL positive. A recent review from Beirut reported that individuals with positive aPL are 11 times more likely to suffer seizures.[13]

Movement disorders

Our original papers in 1983 included cases suffering from chorea. We now know that all kinds of movement disorders, from tics to Parkinson-like tremors, can be seen: Again, a neurological disorder which frequently improves on anti-coagulant treatment.

Multiple sclerosis

With features ranging from balance and visual problems through to transverse myelopathy (back to our Jamaica studies), it is not surprising that a number of our APS patients are initially diagnosed as multiple sclerosis.[14] This is an area where ‘further studies are needed’. Anecdotally, some of our patients with this clinical picture improve with anti-coagulation.

Paroxysmal orthostatic tachycardia syndrome

Recently, we published a series of Hughes syndrome patients who also had paroxysmal orthostatic tachycardia syndrome.[15]

The link between Hughes syndrome and autonomic nerve dysfunction is not surprising, considering that peripheral nerve involvement in Hughes syndrome is well-described.

Rheumatology

There are at least four rheumatology/orthopaedic scenarios linked to Hughes syndrome.

Fractures – Some years ago, Dr Shirish Sangle, one of my team at St Thomas’ Hospital, London, published a series of APS patients with idiopathic metatarsal fractures (‘March fractures’).[16] Since then, a number of other ‘idiopathic’ bone fractures have been reported – sometimes multiple. My colleague Prof Munther Khamashta has one APS patient with 34 such fractures

Hip pain – (often bilateral) is not uncommon in APS patients. Often this progresses to complete avascular necrosis, while in others, the early lesions are only picked up on MRI[7]

Other avascular lesions – clinical reports have included cases of wrist and ankle necrosis

Inflammatory arthritis – a significant number of Hughes syndrome patients also have associated Sjogren's syndrome, which itself can result in inflammatory arthritis.[17]

Cardiovascular System

Ischaemic heart disease – A number of Hughes syndrome patients present with angina. Recent studies have suggested that in younger (e.g., under 45) females with acute coronary syndrome positive tests for aPL are found in up to 40% of patients[18],[19]

‘Syndrome X’ – Syndrome X is a cardiac condition characterised by the presence of angina, but with normal-looking coronaries on angiography. Not surprisingly, this pattern has been seen in a number of patients with Hughes syndrome[20]

Heart valve lesions – mitral and aortic valve lesions are seen in some patients with Hughes syndrome (another distinguishing feature from other clotting disorders). The lesions range from the mild (echocardiography or auscultation) to very severe, requiring cardiac surgery.[21]

Skin

Livedo reticularis is an important feature of Hughes syndrome and a significant diagnostic clue.[22] In other patients, skin thrombosis – especially in the lower limbs – can lead to chronic leg ulcers. These can heal when careful anti-coagulation is started. In some cases, the problem follows a DVT.

An unusual, but diagnostically useful sign in some patients is the presence of nail fold ‘splinter’ haemorrhages.

Kidney

Widespread microthrombosis can occur in the kidney, sometimes as part of the widespread thrombotic ‘storm’ known as the ‘catastrophic APS’.[23]

Renal vein thrombosis was the presenting manifestation of one of the three patients presented in 1982 at the UK rheumatology ‘Heberden Round’. Classically, it presents with renal pain and prominent proteinuria.

Renal artery involvement is interesting. A number of patients have developed renal artery stenosis with secondary hypertension – arterial stenoses now being recognised in a number of sites including the brain and the gastrointestinal tract.[24]

Gastrointestinal Tract

We have seen infarction of whole lengths of bowel in rare cases of Hughes syndrome. A number of patients have developed mesenteric and coeliac artery stenosis leading in some to classical ‘abdominal angina’. The hepatic blood vessels can become involved, leading to abnormal liver function tests, and more widespread hepatic thrombosis. Hughes syndrome is now recognised as an important cause of the Budd–Chiari syndrome.[25]

Other Manifestations

Perhaps surprisingly, thrombocytopenia is a feature in some patients with ‘sticky blood’.

Platelet counts often hover in the ‘borderline’ range of 90,000–110,000, but occasionally, acute thrombocytopenia can be a complication.[26]

Other organs affected have included the adrenal (adrenal thrombosis is sometimes a complicating feature of ‘catastrophic APS’), the testis, the ovary, the pancreas and lungs (pulmonary hypertension is a recognised complication of the Hughes syndrome).[27]

Treatment

Hughes syndrome antiphospholipid syndrome

For ‘milder’ cases, aspirin alone is often sufficient (or clopidogrel if aspirin is contraindicated). For example, in much of the late 1980s and 1990s, aspirin alone was generally the treatment for women in pregnancy who had suffered multiple previous APS miscarriages, and the pregnancy success rate certainly improved. Nowadays, a combination of aspirin and low-molecular-weight heparin is usually the preferred choice.[28]

For patients with severe migraine headaches, balance problems and transient ischaemic attacks, for example, aspirin alone is often unsuccessful.

Heparin

Low-molecular-weight heparin has replaced ‘old’ heparin, and with it, the risks of thrombocytopenia and osteoporosis have largely disappeared.

As well as its more established uses – the immediate treatment of thrombosis and the use in APS pregnancy – heparin has, in my view, become an important diagnostic tool.

Imagine a patient with worsening APS – for example, with very frequent migraines, balance problems, deteriorating memory – clearly not responding to aspirin. Do you go straight to warfarin – in a patient with no over thrombosis history?

My practice in this situation: a short 3-week therapeutic trial, for example, dalteparin (Fragmin) 5,000 – 10,000 units s/c daily (or Clexane). I have found this to be one of the most useful therapeutic trials in my practice. The effect is often clear-cut– ‘no change’ or ‘very successful’. Perhaps a ‘yes’ to warfarin.[29]

Warfarin

Patients with Hughes syndrome often seem to require a higher INR than the usual 2.5–3 seen in anti-coagulant clinics. Intriguingly, APS patients – especially those with neurological disease – often ‘know their INR’. For example, a return of ‘brain fog’ when the INR falls from, say, 3.8–3. A small number of my patients run a steady and asymptomatic course with an INR of 4. One of my strong beliefs is, where possible, the use of a finger-prick self-testing machine (used in collaboration with the patient's anti-coagulation clinic).[7]

New oral anti-coagulation

The past decade has seen the introduction of a series of novel oral anti-coagulants such as edoxaban, fondaparinux and rivaroxaban.

To date, there has been a reluctance to use those drugs in Hughes syndrome, and comparisons with warfarin have been indecisive. However, the number of patients with Hughes syndrome treated with these agents is increasing, and a more balanced appraisal will be possible.

Tests for Hughes syndrome

There are currently three blood tests available:

Anti-cardiolipin antibodies (aCL)

Lupus anti-coagulant (LA)

Anti-beta 2 GP1 antibodies (anti B2 GP1).

Anti-cardiolipin antibodies

The most convenient and reliable. Both immunoglobulin G and immunoglobulin M aCL antibodies are usually measured, though occasional patients only show positive for IgA aCL antibodies.

In general, higher titres relate to more aggressive disease, though in practice, there are many exceptions, for example, cases of severe APS with ‘borderline’ aCL levels.

Lupus anti-coagulant

This unfortunate (historical) title causes confusion (‘do I have lupus?’). Positive LA tests currently found in 70%–80% of APS patients. Because transient positive tests are sometimes seen during acute infections, the current recommendation in to repeat the tests 12 weeks later. I personally disagree with this advice for two reasons. First because the clinical picture usually makes clear the relevance of a positive test, and second, a return visit at 12 weeks is often impractical or too expensive.[30]

Anti-beta 2 GP1

A major breakthrough came with the finding that “anti-phospholipid antibodies” were not directed at phospholipids alone, but to a complex molecule which included a protein. (The original protein was Beta 2 GP1, but others such as prothrombin have since been reported).

This test, like the others, can, in some cases, be the only positive, and hence is now included in most screening protocols.

Sero-negative APS

Some years ago, my colleague Munther Khamashta and I introduced the title ‘sero-negative APS’, but with negative tests.[31] We likened this scenario to the historical description of ‘sero-negative rheumatoid arthritis’ and later, ‘sero-negative lupus’.

We felt that the most likely explanation for this situation was the inadequacy of current tests. That this is the most likely reason is suggested be an important recent paper which applied a battery of newer tests to sera from ‘sero-negative’ patients and found a significant increase in ‘sero-positivity’.[32]

Hughes syndrome antiphospholipid syndrome

Where were all these patients before? Possibly attending neurology, cardiology, rheumatology and other clinics, and in pregnancy, undiagnosed. One of the joys of treating this ‘new’ syndrome is the often surprising improvement when correct treatment is started.

The figures speak for themselves. For example, Hughes syndrome is the commonest, treatable cause of recurrent miscarriage, a fact which has altered the face of obstetrics.

And the future? At the 14th International aPL meeting in Rio, I was asked to give my forecasts, which I repeat here:

aPL testing will become worldwide and routine

Over-the-counter aPL testing kits will become available (and the dreaded ‘lupus anti-coagulant’ test will become obsolete)

New hope for migraine sufferers with the realisation that Hughes syndrome/APS is significant cause

APS/Hughes syndrome will be finally recognised as the chief missing link between migraine and stroke

The incidence of stillbirth will be greatly reduced – largely because of the routine checks for aPL

Young heart attacks, especially in women under 45, will be reduced, with aPL being recognised as a greater risk factor than cholesterol

Strokes in under 45s will be reduced following the worldwide recognition of aPL as a risk factor for stroke and transient ischaemic attacks

A subset of aPL-positive patients will be identified in whom there is a clear risk of accelerated arterial disease

Memory loss – some cases are treatable

And in lupus? There will be a widespread recognition that the discovery of the syndrome has profoundly altered our management. Not all patients with lupus require steroids – in many, the problem may be more one of dealing with ‘sticky blood’.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

Top

1.

Hughes GR. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. Br Med J (Clin Res Ed) 1983;287:1088-9. Back to cited text no. 1

2.

Boey ML, Colaco CB, Gharavi AE, Elkon KB, Loizou S, Hughes GR, et al. Thrombosis in systemic lupus erythematosus: Striking association with the presence of circulating lupus anticoagulant. Br Med J (Clin Res Ed) 1983;287:1021-3. Back to cited text no. 2

3.

Harris EN, Gharavi AE, Boey ML, Patel BM, Mackworth-Young CG, Loizou S, et al. Anticardiolipin antibodies: Detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983;2:1211-4. Back to cited text no. 3

4.

Hughes GR. The prosser-white oration 1983. Connective tissue disease and the skin. Clin Exp Dermatol 1984;9:535-44. Back to cited text no. 4

5.

Bresnihan B, Oliver M, Grigor R, Hughes GR. Brain reactivity of lymphocytotoxic antibodies in systemic lupus erythematosus with and without cerebral involvement. Clin Exp Immunol 1977;30:333-7. Back to cited text no. 5

6.

Bresnihan B, Grigor RR, Hughes GR. Lymphocytotoxic antibodies in systemic lupus erythematosus: Their clinical significance. J Clin Pathol Suppl (R Coll Pathol) 1979;13:112-5. Back to cited text no. 6

7.

Hughes GR. Hughes syndrome/APS 30 years on, what have we learnt? Opening talk at the 14th International Congress on Antiphospholipid Antibodies Rio de Janiero, October 2013. Lupus 2014;23:400-6. Back to cited text no. 7

8.

Di Simone N, Meroni PL, de Papa N, Raschi E, Caliandro D, De Carolis CS, et al. Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered beta2-glycoprotein I. Arthritis Rheum 2000;43:140-50. Back to cited text no. 8

9.

Nencini P, Baruffi MC, Abbate R, Massai G, Amaducci L, Inzitari D, et al. Lupus anticoagulant and anticardiolipin antibodies in young adults with cerebral ischemia. Stroke 1992;23:189-93. Back to cited text no. 9

10.

Hughes GR. Migraine, memory loss, and “multiple sclerosis”. Neurological features of the antiphospholipid (Hughes') syndrome. Postgrad Med J 2003;79:81-3. Back to cited text no. 10

11.

Hughes GR, Cuadrado MJ, Khamashta MA, Sanna G. Headache and memory loss: Rapid response to heparin in the antiphospholipid syndrome. Lupus 2001;10:778. Back to cited text no. 11

12.

Noureldine MH, Haydar AA, Berjawi A, Elnawar R, Sweid A, Khamashta MA, et al. Antiphospholipid syndrome (APS) revisited: Would migraine headaches be included in future classification criteria? Immunol Res 2017;65:230-41. Back to cited text no. 12

13.

Noureldine MH, Harifi G, Berjawi A, Haydar AA, Nader M, Elnawar R, et al. Hughes syndrome and epilepsy: When to test for antiphospholipid antibodies? Lupus 2016;25:1397-411. Back to cited text no. 13

14.

Ferreira S, D'Cruz DP, Hughes GR. Multiple sclerosis, neuropsychiatric lupus and antiphospholipid syndrome: Where do we stand? Rheumatology (Oxford) 2005;44:434-42. Back to cited text no. 14

15.

Schofield JR, Blitshteyn S, Shoenfeld Y, Hughes GR. Postural tachycardia syndrome (POTS) and other autonomic disorders in antiphospholipid (Hughes) syndrome (APS). Lupus 2014;23:697-702. Back to cited text no. 15

16.

Sangle S, D'Cruz DP, Khamashta MA, Hughes GR. Antiphospholipid antibodies, systemic lupus erythematosus, and non-traumatic metatarsal fractures. Ann Rheum Dis 2004;63:1241-3. Back to cited text no. 16

17.

Hughes GR, Sangle S, Bowman S. Sjogren's Syndrome in Clinical Practice. London: Springer; 2014. Back to cited text no. 17

18.

Greco T, Conti-Kelly A, Greco T Jr. Newer antiphospholipid antibodies predict acute adverse outcome in patients with acute coronary syndrome. Coagul Tranfus Med 2009;132:613-20. Back to cited text no. 18

19.

Urbanus RT, Siegerink B, Roest M, Rosendaal FR, de Groot PG, Algra A, et al. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: A case-control study. Lancet Neurol 2009;8:998-1005. Back to cited text no. 19

20.

Nair S, Khamashta MA, Hughes GR. Syndrome X and Hughes syndrome. Lupus 2002;11:332. Back to cited text no. 20

21.

Englert HJ, Loizou S, Derue GG, Walport MJ, Hughes GR. Clinical and immunologic features of livedo reticularis in lupus: A case-control study. Am J Med 1989;87:408-10. Back to cited text no. 21

22.

Khamashta MA, Cervera R, Asherson RA, Font J, Gil A, Coltart DJ, et al. Association of antibodies against phospholipids with heart valve disease in systemic lupus erythematosus. Lancet 1990;335:1541-4. Back to cited text no. 22

23.

Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. Antiphospholipid syndrome: Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46:1019-27. Back to cited text no. 23

24.

Sangle S, D'Cruz D, Khamashta M, Tungekar MF, Abbs I, Hughes G, et al. Goldblatt's kidney, Hughes syndrome and hypertension. Lupus 2002;11:699-703. Back to cited text no. 24

25.

Yasutomi M, Egawa H, Kobayashi Y, Oike F, Tanaka K. Living donor liver transplantation for Budd-Chiari syndrome with inferior vena cava obstruction and associated antiphospholipid antibody syndrome. J Pediatr Surg 2001;36:659-62. Back to cited text no. 25

26.

Harris EN, Asherson RA, Gharavi AE, Morgan SH, Derue G, Hughes GR, et al. Thrombocytopenia in SLE and related autoimmune disorders: Association with anticardiolipin antibody. Br J Haematol 1985;59:227-30. Back to cited text no. 26

27.

Asherson RA, Mackworth-Young CG, Boey ML, Hull RG, Saunders A, Gharavi AE, et al. Pulmonary hypertension in systemic lupus erythematosus. Br Med J (Clin Res Ed) 1983;287:1024-5. Back to cited text no. 27

28.

Lakasing L, Bewley S, Nelson-Piercy C. Hughes syndrome: antiphospholipid. In: Khamashta MA, editor. Management of Antiphospholipid Syndrome in Pregnancy. 2nd ed. London: Springer; 2012. Back to cited text no. 28

29.

Hughes GR. Heparin, antiphospholipid antibodies and the brain. Lupus 2012;21:1039-40. Back to cited text no. 29

30.

Hughes GR. Lupus around the world. Lupus 2015;24:1-3. Back to cited text no. 30

31.

Hughes GR, Khamashta MA. Seronegative antiphospholipid syndrome. Ann Rheum Dis 2003;62:1127. Back to cited text no. 31

32.

Zohoury N, Bertolaccini ML, Rodriguez-Garcia JL, Shums Z, Ateka-Barrutia O, Sorice M, et al. Closing the serological gap in the antiphospholipid syndrome: The value of “Non-criteria” antiphospholipid antibodies. J Rheumatol 2017;44:1597-602. Back to cited text no3

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