Diagnosis and management of the antiphospholipid syndrome
BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.c2541 (Published 14 May 2010) Cite this as: BMJ 2010;340:c2541All rapid responses
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"Doctors believe to greatly benefit a patient by giving his illness a
name" (Immanuel Kant).
The benefit of the label "antiphospholipid syndrome" remains undefined,
except for generating publications (over 9000 hits in MedLine for
"antiphospholipid"). It is still uncertain how treatment should differ for
patients with "antiphospholipid syndrome" (disease and positive
"antiphospholipid" antibody tests) from patients without (disease and
negative tests).
Syndrome-defining criteria (1), both clinical and laboratory, are
complex, but still leave considerable room for variable interpretation,
and for dissense. Criteria are based on limited consensus, reflecting
contradictory evidence from many studies - done in variably selected
patients, with variable tests that correlate poorly and that lack an
established comparator, and with relation of such test results to variably
defined outcomes. Basic mechanisms and paradoxes remain unexplained, eg.
how do some "antiphospholipid" antibodies prolong some coagulation tests
in vitro ("lupus anticoagulant" effect) and at the same time favor blood
clotting in vivo ?
Few conclusions can be drawn firmly, but one merits emphasis. The
syndrome's umbrella covers extraordinary heterogeneity, of antibody
target(s), epitope(s) and pathomechanism(s); of test principles,
performance and interpretation; and of associated disease(s). Such
heterogeneity defies the scientific principles of reproducibility and
falsifiability; a hypothesis that cannot be falsified is "not even wrong".
The concept of "antiphospholipid syndrome" needs overhaul, re- or
deconstruction, to become amenable to a scientific approach. Discussion
and progress will be stimulated more likely by pro-con format debate (eg.
"Testing for antiphospholipid antibodies benefits patients"), than by
adding another review to those 2000 already published.
It requires considerable efforts to keep up to date, and considerable
time to counsel those concerned and confused, patients and colleagues.
Studies of higher quality (2-4) generally report much less, or no,
significance of "antiphospholipid" antibodies, compared to the many
studies with less stringent methods. As long as stronger evidence is
lacking, the main themes of counseling will remain: a) that and why the
significance of "antiphospholipid" tests is at best uncertain, and b) to
agree on a treatment plan based more on clinical than on laboratory
factors.
References:
(1) Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R,
Derksen RH,
DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A,
Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an
update
of the classification criteria for definite antiphospholipid syndrome
(APS). J
Thromb Haemost. 2006 Feb;4(2):295-306.
(2) Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis
J, Laskin C,
Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D,
Costantini
L, Yacura W, Wilson S, Gent M, Kovacs MJ. A comparison of two intensities
of
warfarin for the prevention of recurrent thrombosis in patients with the
antiphospholipid antibody syndrome. N Engl J Med. 2003 Sep 18;349(12):1133
-8.
(3) Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F,
Musial J, Baudo F,
Berrettini M, Testa S, D'Angelo A, Tognoni G, Barbui T. A randomized
clinical
trial of high-intensity warfarin vs. conventional antithrombotic therapy
for the
prevention of recurrent thrombosis in patients with the antiphospholipid
syndrome
(WAPS). J Thromb Haemost. 2005 May;3(5):848-53.
(4) Levine SR, Brey RL, Tilley BC, Thompson JL, Sacco RL, Sciacca RR,
Murphy A, Lu
Y, Costigan TM, Rhine C, Levin B, Triplett DA, Mohr JP; APASS
Investigators.
Antiphospholipid antibodies and subsequent thrombo-occlusive events in
patients
with ischemic stroke. JAMA. 2004 Feb 4;291(5):576-84.
Competing interests:
None declared
Competing interests: No competing interests
We very much appreciate your rapid response to our review, which
highlights some of the most essential difficulties surrounding this
complicated syndrome.
Firstly, even though we fully agree that antiphospholipid syndrome
will occur rarely in a consulting room of a general practitioner, these
patients will present with commonly occurring symptoms in the general
practitioners practice. The history and physical examination will indeed
provide the clues indicating that there may more to the seemingly straight
forward deep vein thrombosis, fetal loss or transient ischemic attack in a
particular patient. We hope that the signs and symptoms in figure 2 and
box 3 of the review are of assistance in detecting the patients in whom
the antiphospholipid syndrome should be included in the differential
diagnosis.
Due to the large variation in clinical presentation, and the
difficulty of unspecific serological tests, the exact population
prevalence numbers have proved difficult, if not impossible to establish.
We agree that false positivity is the biggest pitfall when testing for
antiphospholipid antibodies. We also realize the price of a false positive
diagnosis can be high: potentially unnecessary indefinite
thromboprophylaxis with all its risks and side effects.
It is up to the general practitioner to decide if he wants to test
himself, or refer to secondary care depending on the local situation and
personal preference.
In response to Dr Breen
We thank Dr Breen and colleagues for their useful addition to our
paper and we agree that the treatment of patients with antiphospholipid
syndrome and an arterial event is still controversial. Until well designed
prospective studies are performed the final word on this subject is
difficult, if not impossible to obtain.
Therefore, we want to restate our point of the treatment strategies of
such patients being designed by a multidisciplinary team with experience
with the disease to maximize the individualization of the treatment in
line with disease activity and patient’s preferences.
In response to Dr Farmer
We are most thankful for your rapid response, which touches an
important issue to which we did not extensively comment in our review. We
fully agree with your recommendations on the use of safe and effective
contraception in SLE and antiphospholipid syndrome, that are compatible
with the WHO Medical Eligibility Criteria for Contraceptive Use.
On behalf of all co-authors,
Yours sincerely,
Danielle Cohen
Competing interests:
None declared
Competing interests: No competing interests
Cohen et al(1) discuss how adverse pregnancy outcomes may be
prevented
in anti-phospholipid syndrome (APS). However not all women with this
syndrome will want to become pregnant and so effective, safe contraception
must be considered. The Faculty of Sexual and Reproductive Health care
produce recommendations on the use of contraceptive methods within
different clinical settings(2). Their guidance is a UK adaptation of a
World
Health Organisation document(3) and was updated in 2009. Both the WHO
and UK versions describe the use of estrogen-containing contraception in
SLE
and APS as an "unacceptable health risk",due to the increased risk of
venous
thrombosis. Therefore, use of the combined pill, patch and vaginal ring
should be avoided. Progestogen-only methods are not recommended also,
as "their risks usually outweigh the advantages". If reliable
contraception is
desired, the only remaining option is the copper-bearing intra-uterine
device
(IUD) but this may not be acceptable to every woman. Thus choices are
limited for women wanting to avoid pregnancy. Condoms and female barrier
methods may be used but are far from ideal owing to their relatively
higher
failure rates.
1.Cohen, D et al, Diagnosis and management of the anti-phospholipid
syndrome. BMJ 2010; 340:c2541
2. UK Medical Eligibility Criteria for Contraceptive Use 2009
http://www.ffprhc.org.uk/admin/uploads/UKMEC2009.pdf
3. WHO Medical Eligibility Criteria for Contraceptive Use 2009
Available at:
http://whqlibdoc.who.int/publications/2009/9789241563888_eng.pdf
Competing interests:
None declared
Competing interests: No competing interests
Letter to the editor
Cohen et al provide an overview of the diagnosis and management of
the antiphospholipid Syndrome(APS)[1] and focus briefly on the treatment
of arterial thrombosis in patients with APS. While the treatment of a
first unprovoked venous thrombosis in the setting of persistent
antiphospholipid antibodies agreeably is long term anticoagulation at a
target INR range between 2-3, treatment of arterial thrombosis however,
has notoriously been more controversial due to lack of prospective studies
in this group. We advocate that patients with arterial thrombosis be
anticoagulated at a higher intensity long term to maintain an INR range
between 3-4.
Most of the basis of the recommendations for treatment with higher
intensity warfarin in patients with arterial events associated with
antiphospholipid antibodies comes from retrospective reviews of patient
cohorts[2-4]. These studies all come to similar conclusions – that higher
intensity warfarin is superior to standard treatment. A recent systematic
review of secondary thromboprophylaxis in patients with antiphospholipid
antibodies showed patients with arterial thrombosis treated with
higher intensity warfarin(target INR range 3-4)rarely experience recurrent
events [5]. Bleeding rates
appear to be similar in patients on higher intensity warfarin in
comparison to standard treatment[5].
There are only 2 prospective studies of higher intensity warfarin in
patients with APS and these studies have many limitations. In the APASS
study, patients with cerebral arterial events and antiphospholipid
antibodies were randomised to warfarin versus aspirin which concluded
recurrent events and bleeding episodes were similar in both
groups[6].Patients recruited to this study were only tested on one
occasion for antiphospholipid antibodies therefore did not fulfil the
criteria for APS, and patients on higher intensity warfarin had a
subtherapeutic INR for 41% of the time. The other prospective study in
patients with antiphospholipid syndrome and recurrent
thrombosis(WARSS study) involved randomisation of patients to high
intensity warfarin (INR 3-4) versus standard treatment[7]. This concluded
no difference between higher intensity warfarin and standard treatment yet
most of the patients recruited to the study had only a previous venous
thrombotic event. Unfortunately neither of these studies are of use in
clinical practise for management of patients with APS.
Although there is evidence for the use of aspirin as secondary
thromboprophylaxis in stroke in the general population, there is little
evidence for the use of aspirin alone in patients with a previous arterial
event and APS. The APASS study is the only study in this setting and has
limitations for the reasons discussed above. In particular, some recommend
aspirin in the setting of non cardio-embolic cerebral thrombosis. Again,
there is little evidence for this and eliminating a cardiac source of
cerebral thrombosis can prove particularly difficult since current
diagnostic tests have limited
sensitivities.
Treatment of arterial events in patients with APS continues to be a
controversial subject and more
prospective studies are definitely required, but for now, we recommend
treatment with higher intensity anticoagulation in patients with APS and
a previous arterial event.
References
1.Cohen, D., et al., Diagnosis and management of the antiphospholipid
syndrome. BMJ.340:c2541.
2.Khamashta, M.A., et al., The management of thrombosis in the
antiphospholipid-antibody syndrome. N Engl J Med, 1995.332:993-7.
3.Ruiz-Irastorza, G., et al., Bleeding and recurrent thrombosis in
definite antiphospholipid syndrome: analysis of a series of 66 patients
treated with oral anticoagulation to a target international normalized
ratio of 3.5. Arch Intern Med, 2002. 162:1164-9.
4.Rosove, M.H. and P.M. Brewer, Antiphospholipid thrombosis: clinical
course after the first thrombotic event in 70 patients. Ann Intern Med,
1992. 117:303-8.
5.Ruiz-Irastorza, G., B.J. Hunt, and M.A. Khamashta, A systematic review
of secondary thromboprophylaxis in patients with antiphospholipid
antibodies. Arthritis Rheum, 2007. 57:1487-95.
6.Levine, S.R., et al., Antiphospholipid antibodies and subsequent thrombo
-occlusive events in patients with ischemic stroke. JAMA, 2004. 291:576-
84.
7.Finazzi, G., et al., A randomized clinical trial of high-intensity
warfarin vs. conventional antithrombotic therapy for the prevention of
recurrent thrombosis in patients with the antiphospholipid syndrome
(WAPS). J Thromb Haemost, 2005. 3:848-53.
Breen KA(1,2), Khamashta M(2), Hunt B.J.(1,2)
Departments of Thrombosis and Haemostasis (1), and Lupus Unit(2),Guys and
St.Thomas’s NHS Foundation Trust, London, UK.
Correspondence to: karen.breen@gstt.nhs.uk
Competing interests:
None declared
Competing interests: No competing interests
Dear Madam or Sir,
As a general practitioner - and therefore one of the non-specialists
specifically addressed by the authors - I read the recent clinical review
on antiphospholipid syndrome with interest. The content was informative
and prompted me to favour only one of the 'basic guiding principles'
provided by the authors.
I'll use three different sets of pegs on which to hang my comments:
the paper's summary points and tips for non-specialists and my own disease
checklist. I'll follow with the my own guiding principle.
The summary points when paraphrased are that the syndrome is
dangerous and can affect virtually any system, that the lupus
anticoagulant test is most useful because positivity correlates most
strongly with clinical manifestations and that particular features are
more important or common than others. These tips use patients with the
syndrome as the denominator whereas in my consulting room they consitute a
rare numerator.
The tips for non-specialists reaffirm that the syndrome is dangerous,
that it is important to diagnose without delay and that we should obtain
the results of the test before starting treatment. However, in the body of
the paper we learn that tests must be repeated after at least 12 weeks to
reduce the high false positive rate. In the meantime, treatment is
determined by what I might call the primary diagnosis - such as stroke or
deep vein thrombosis - and which the authors relegate to the 'second hit'.
We non-specialists are advised to perform three laboratory tests. We are
not given the positive likelihood ratios or positive predictive values but
I would guess these are low given that elsewhere in the paper we are told
that one of the tests has a laboratory false positive rate of 24% and a
positive rate in the population of 1-5%. We also learn elsewhere that in
the clinically normal population prognostic significance of a positive
test result is unknown. We are advised to refer to a specialist, advise
about lifestyle and avoid thrombogenic drugs.
My own disease checklist prompts the following observations. The
epidemiology outwith SLE is unclear, the aetiology is unknown, clinical
features are non specific, pathology is not understood, tests are
unreliable, the diagnosis is generally made many weeks after the acute
event, management is largely determined by the primary diagnosis
(clinically the 'first hit') and, while prognosis importantly can be
improved for a small number who definitely have the syndrome and are under
specialist care, there is scope for the non-specialist to do much harm to
those with false positive diagnoses.
The paper is written, like much medical literature, with the
diagnosis as the starting point whereas clinical practice begins with a
symptom or sign.
I think the syndrome is likely to present to me as a thrombotic event
or worry about a family history. In either case I suspect the best course
of action is a good clinical history and examination followed if necessary
by referral to secondary care, acutely or electively as indicated. For me
to initiate investigations would likely do more harm than good.
Yours sincerely,
Wilfrid Treasure
Competing interests:
None declared
Competing interests: No competing interests
Re: Diagnosis and management of the antiphospholipid syndrome
Antiphospholipid syndrome is recurrent venous and arterial thrombosis with foetal loss. Trigger mechanism and therapeutics principles are yet to be completely ascertained. Novel ideas of recognition are activation of beta – 2 – glycoprotein 1 antibodies, complement activation. Although there are no racial dominance of primary antiphospholipid syndrome Female dominance are elicited the heterogeneity of its presentation allows us to think about multiple pathophysiology involved. Currently there are no biomarkers to predict the prognosis (1).Patients with lupus anticoagulant, high titre ACL IgG, LA or ACL with anti-B2 GPI antibodies have the highest thrombotic risk.
Most common venous presentation is the deep vein thrombosis and arterial thrombosis is the stroke. Pregnancy related complication involves pre-eclampsia, premature birth, early and late foetal loss (2). Non thrombotic manifestations involve neurologic manifestations like cognitive dysfunction and emylination.Pulmonary capillaritis leads to diffuse alveolar haemorrhage. In case of life threatening APS the early therapies are – plasma exchange ,intravenous immunoglobulin and parenteral steroids .An interesting group is the one with all classical features of APS but negative blood test.But , they also need anticoagulation (3).
Treatment in respect to venous thrombosis is to keep INR 2.0 – 3.0 (4) and in arterial thrombosis > 3.0 (5).More data is necessary to translate the changes in understanding mechanism and management.
Reference:
1.Cuadrado Mj,Aguirre MA,Bartarroja N,Khamastha MA, Lopez Pedera CH. Proteomics in antiphospholipid syndrome : a review .Lupus 2010 Apr ,19(4) , 385 -8.
2.Cervera .Lessons from the ‘Euro –phospholipid ‘project .Autoimmune Rev.2008; 7:174 -178.
3.Ruiz-Irastorza G, Khamastha MA. The treatment of antiphospholipid syndrome: a harmonic contrast > Best Pract Res Clinic Rheumatol 247, 21:1079 -1092.
4.Ruiz-Irastorza G,Hunt BJ,Khamastha MA.A systematic review of secondary thromboprphylaxis inpatients with antiphospholipid antobodies.Arthritis Rheum 2007 ;57 : 1487 – 1495.
5.Hughes GP.Hughes syndrome (the antiphospholipid syndrome): ten clinical lesson.Autoimmun Rev .2008; 7:262 – 266.
Competing interests: No competing interests