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Antiphospholipid syndrome

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Title: Antiphospholipid syndrome  
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Subject: Systemic lupus erythematosus, Apolipoprotein H, Deep vein thrombosis, Thrombocytopenia, Anti-nuclear antibody
Collection: Autoimmune Diseases, Coagulopathies, Neurological Disorders, Obstetrics, Rheumatology, Syndromes
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Antiphospholipid syndrome

Antiphospholipid syndrome
Micrograph showing an advanced thrombotic microangiopathy, as may be seen in ALPA syndrome. Kidney biopsy. PAS stain.
Classification and external resources
Specialty Rheumatology
ICD-10 D68.6 (ILDS D68.810)
ICD-9-CM ICD9 289.81
OMIM 107320
DiseasesDB 775
eMedicine med/2923
MeSH D016736

Antiphospholipid syndrome or antiphospholipid antibody syndrome (APS or APLS), or often also Hughes syndrome, is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS provokes blood clots (thrombosis) in both arteries and veins as well as pregnancy-related complications such as miscarriage, stillbirth, preterm delivery, and severe preeclampsia.

The diagnostic criteria require one clinical event, i.e. thrombosis or pregnancy complication, and two antibody blood tests spaced at least three months apart that confirm the presence of either lupus anticoagulant, or anti-β2-glycoprotein-I (since β2-glycoprotein-I antibodies are a subset of anti-cardiolipin antibodies, an anti-cardiolipin assay can be performed as a less specific proxy)[1]

Antiphospholipid syndrome can be primary or secondary. Primary antiphospholipid syndrome occurs in the absence of any other related disease. Secondary antiphospholipid syndrome occurs with other autoimmune diseases, such as catastrophic antiphospholipid syndrome" (CAPS) and is associated with a high risk of death.

Antiphospholipid syndrome often requires treatment with anticoagulant medication such as heparin to reduce the risk of further episodes of thrombosis and improve the prognosis of pregnancy. Warfarin/Coumadin is not used during pregnancy because it can cross the placenta, unlike heparin, and is teratogenic.


  • Signs and symptoms 1
  • Risk factors 2
  • Pathogenesis 3
  • Diagnosis 4
    • Lupus anticoagulant 4.1
    • Anticardiolipin antibodies 4.2
    • Criteria 4.3
  • Treatment 5
  • Prognosis 6
  • History 7
  • Research 8
  • References 9
  • Bibliography 10
  • External links 11

Signs and symptoms

The presence of antiphospholipid antibodies (aPL) in the absence of blood clots or pregnancy-related complications does not indicate APS (see below for the diagnosis of APS).

Antiphospholipid syndrome can cause pregnancy-related complications. In APS patients, the most common venous event is deep vein thrombosis of the lower extremities, and the most common arterial event is stroke. In pregnant women affected by APS, there is an increased risk of recurrent miscarriage, intrauterine growth restriction, and preterm birth.[2] A frequent cause of such complications is placental infarctions. In some cases, APS seems to be the leading cause of mental and/or development retardation in the newborn, due to an aPL-induced inhibition of trophoblast differentiation. The antiphospholipid syndrome responsible for most of the miscarriages in later trimesters seen in concomitant systemic lupus erythematosus and pregnancy.[3]

Other common findings, although not part of the APS classification criteria, are low platelet count, heart valve disease, and livedo reticularis. There are also associations between antiphospholipid antibodies and headaches, migraines, and oscillopsia.[4] Some studies have shown the presence of antiphospholipid antibodies in the blood and spinal fluid of patients with psychological symptoms.[5]

Very few patients with primary APS go on to develop SLE.

Risk factors

Risk factors for developing antiphospholipid syndrome include:


Antiphospholipid syndrome is an autoimmune disease, in which "antiphospholipid antibodies" (anticardiolipin antibodies and lupus anticoagulant) react against proteins that bind to anionic phospholipids on plasma membranes. Like many autoimmune diseases, it is more common in women than in men. The exact cause is not known, but activation of the system of coagulation is evident. Clinically important antiphospholipid antibodies (those that arise as a result of the autoimmune process) are associated with thrombosis and vascular disease. The syndrome can be divided into primary (no underlying disease state) and secondary (in association with an underlying disease state) forms.

Anti-ApoH and a subset of anti-cardiolipin antibodies bind to ApoH, which in turn inhibits Protein C, a glycoprotein with regulatory function upon the common pathway of coagulation (by degradating activated factor V).

Lupus anticoagulant (LAC) antibodies bind to prothrombin, thus increasing its cleavage to thrombin, its active form.

In APS there are also antibodies binding to Protein S, which is a co-factor of protein C. Thus, anti-protein S antibodies decrease protein C efficiency.[6]

Annexin A5 forms a shield around negatively charged phospholipid molecules, thus reducing their availability for coagulation. Thus, anti-annexin A5 antibodies increase phospholipid-dependent coagulation steps.[7]

The Lupus anticoagulant antibodies are those that show the closest association with thrombosis, those that target β2glycoprotein 1 have a greater association with thrombosis than those that target prothrombin. Anticardiolipin antibodies are associated with thrombosis at moderate to high titres (>40 GPLU or MPLU). Patients with both Lupus anticoagulant antibodies and moderate/high titre anticardiolipin antibodies show a greater risk of thrombosis than with one alone.

The increased risks of recurrent miscarriage, intrauterine growth restriction and preterm birth by antiphospholipid antibodies, as supported by in vitro studies, include decreased trophoblast viability, syncytialization and invasion, deranged production of hormones and signalling molecules by trophoblasts, as well as activation of coagulation and complement pathways.[2]


Antiphospholipid syndrome is tested for in the laboratory using both liquid phase coagulation assays (lupus anticoagulant) and solid phase ELISA assays (anti-cardiolipin antibodies).

Genetic thrombophilia is part of the differential diagnosis of APS and can coexist in some APS patients. Presence of genetic thrombophilia may determine the need for anticoagulation therapy. Thus genetic thrombophilia screening can consist of:

The testing of antibodies to the possible individual targets of aPL such as β2 glycoprotein 1 and antiphosphatidyl serine is currently under debate as testing for anticardiolipin appears to be currently sensitive and specific for diagnosis of APS even though cardiolipin is not considered an in vivo target for antiphospholipid antibodies.

Lupus anticoagulant

This is for by using a minimum of two coagulation tests that are phospholipid sensitive, due to the heterogeneous nature of the lupus anticoagulant antibodies. The patient on initial screening will typically have been found to have a prolonged APTT that does not correct in an 80:20 mixture with normal human plasma (50:50 mixes with normal plasma are insensitive to all but the highest antibody levels). The APTT (plus 80:20 mix), dilute Russell's viper venom time (DRVVT), the kaolin clotting time (KCT), dilute thromboplastin time (TDT/DTT) or prothrombin time (using a lupus sensitive thromboplastin) are the principal tests used for the detection of lupus anticoagulant. These tests must be carried out on a minimum of two occasions at least 6 weeks apart and be positive on each occasion demonstrating persistent positivity to allow a diagnosis of antiphospholipid syndrome. This is to prevent patients with transient positive tests (due to infection etc.) being diagnosed as positive.

Distinguishing a lupus antibody from a specific coagulation factor inhibitor (e.g.: Factor VIII). This is normally achieved by differentiating the effects of a lupus anticoagulant on factor assays from the effects of a specific coagulation factor antibody. The lupus anticoagulant will inhibit all the contact activation pathway factors (Factor VIII, Factor IX, Factor XI and Factor XII). Lupus anticoagulant will also rarely cause a factor assay to give a result lower than 35 iu/dl (35%) whereas a specific factor antibody will rarely give a result higher than 10 iu/dl (10%). Monitoring IV anticoagulant therapy by the APTT ratio is compromised due to the effects of the lupus anticoagulant and in these situations is generally best performed using a chromogenic assay based on the inhibition of Factor Xa by antithrombin in the presence of heparin.

Anticardiolipin antibodies

These can be detected using an enzyme-linked immunosorbent assay (ELISA) immunological test, which screens for the presence of β2glycoprotein 1 dependent anticardiolipin antibodies (ACA).

A low platelet count and positivity for antibodies against β2-glycoprotein 1 or phosphatidylserine may also be observed in a positive diagnosis.


Classification with APS requires evidence of both one or more specific, documented clinical events (either a vascular thrombosis and/or adverse obstetric event) and the confirmed presence of a repeated aPL. The Sapporo APS classification criteria (1998, published in 1999) were replaced by the Sydney criteria in 2006.[8] Based on the most recent criteria, classification with APS requires one clinical and one laboratory manifestation:

  • Clinical:
    • A documented episode of arterial, venous, or small vessel thrombosis — other than superficial venous thrombosis — in any tissue or organ by objective validated criteria with no significant evidence of inflammation in the vessel wall, and/or
    • 1 or more unexplained deaths of a morphologically normal fetus (documented by ultrasound or direct examination of the fetus) at or beyond the 10th week of gestation and/or 3 or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded or at least 1 premature birth of a morphologically normal neonate before the 34th week of gestation due to eclampsia or severe pre-eclampsia according to standard definitions, or recognized features of placental insufficiency plus
  • Laboratory:
    • Anti-cardiolipin IgG and/or IgM measured by standardized, non-cofactor dependent ELISA on 2 or more occasions, not less than 12 weeks apart; medium or high titre (i.e., > 40 GPL or MPL, or > the 99th percentile) and/or
    • Anti-β2 glycoprotein I IgG and/or IgM measured by standardized ELISA on 2 or more occasions, not less than 12 weeks apart; medium or high titre (> the 99th percentile) and/or
    • Lupus anticoagulant detected on 2 occasions not less than 12 weeks apart according to the guidelines of the International Society of Thrombosis and Hemostasis.

There are 3 distinct APS disease entities: primary (the absence of any comorbidity), secondary (when there is a pre-existing autoimmune condition, most frequently systemic lupus erythematosus, SLE), and catastrophic (when there is simultaneous multi-organ failure with small vessel occlusion).

According to a 2006 consensus statement,[9] it is advisable to classify APS into one of the following categories for research purposes:

  • I: more than one laboratory criterion present in any combination;
  • IIa: lupus anticoagulant present alone
  • IIb: anti-cardiolipin IgG and/or IgM present alone in medium or high titers
  • IIc: anti-β2 glycoprotein I IgG and/or IgM present alone in a titer greater than 99th percentile

The International Consensus Statement is commonly used for Catastrophic APS diagnosis.[10] Based on this statement, Definite CAPS diagnosis requires:

  • a) Vascular thrombosis in three or more organs or tissues and
  • b) Development of manifestations simultaneously or in less than a week and
  • c) Evidence of small vessel thrombosis in at least one organ or tissue and
  • d) Laboratory confirmation of the presence of aPL.

VDRL, which detects antibodies against syphilis, may have a false positive result in aPL-positive patients (aPL bind to the lipids in the test and make it come out positive), although the more specific test for syphilis, FTA-Abs, that use recombinant antigens will not have a false-positive result.


Often, this disease is treated by giving aspirin to inhibit platelet activation, and/or warfarin as an anticoagulant. The goal of the prophylactic treatment with warfarin is to maintain the patient's INR between 2.0 and 3.0.[11] It is not usually done in patients who have had no thrombotic symptoms.

Anticoagulation appears to prevent miscarriage in pregnant women.[12] In pregnancy, low molecular weight heparin and low-dose aspirin are used instead of warfarin because of warfarin's teratogenicity. Women with recurrent miscarriage are often advised to take aspirin and to start low molecular weight heparin treatment after missing a menstrual cycle. In refractory cases plasmapheresis may be used.


The long-term prognosis for APS is determined mainly by recurrent thrombosis, which may occur in up to 29% of patients, sometimes despite antithrombotic therapy.


Antiphospholipid syndrome was described in full in the 1980s, after various previous reports of specific antibodies in people with systemic lupus erythematosus and thrombosis.[13][14] The syndrome is sometimes referred to as "Hughes syndrome", after the rheumatologist Graham R.V. Hughes (St. Thomas' Hospital, London, UK) who worked at the Louise Coote Lupus Unit at St Thomas' Hospital in London and at the London Lupus Centre at London Bridge Hospital, playing a central role in the description of the condition.[14][15]


APS ACTION (the AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking), is the first-ever international research network that has been created to design and conduct large-scale, multicenter clinical trials in persistently antiphospholipid antibody (aPL) positive patients.[16] The network consists of a multidisciplinary group of physicians and investigators from around the world who are interested in antiphospholipid syndrome (APS) research. The primary mission of APS ACTION is to prevent, treat, and cure antiphospholipid antibody (aPL) associated clinical manifestations through high quality, multicenter, and multidisciplinary clinical research.


  1. ^ "Aps | Action". Retrieved 2013-11-06. 
  2. ^ a b Tong, M.; Viall, C. A.; Chamley, L. W. (2014). "Antiphospholipid antibodies and the placenta: a systematic review of their in vitro effects and modulation by treatment". Human Reproduction Update 21 (1): 97–118.  
  3. ^ Lupus and Pregnancy by Michelle Petri. The Johns Hopkins Lupus Center. Retrieved May 2011
  4. ^ Rinne T, Bronstein AM, Rudge P, Gresty MA, Luxon LM (1998). "Bilateral loss of vestibular function: clinical findings in 53 patients". J. Neurol. 245 (6–7): 314–21.  
  5. ^ Sokol DK, O'Brien RS, Wagenknecht DR, Rao T, McIntyre JA (2007). "Antiphospholipid antibodies in blood and cerebrospinal fluid of patients with psychosis". Journal of Neuroimmunology 190 (1): 151–6.  
  6. ^ Triplett DA (November 2002). "Antiphospholipid antibodies.". Archives of pathology & laboratory medicine 126 (11): 1424–9.  
  7. ^ Rand JH (1998). "Antiphospholipid antibody syndrome: new insights on thrombogenic mechanisms.". The American journal of the medical sciences 316 (2): 142–51.  
  8. ^ 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 (February 2006). "International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)". J. Thromb. Haemost. 4 (2): 295–306.  
  9. ^ 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 (February 2006). "International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)". J. Thromb. Haemost. 4 (2): 295–306.  
  10. ^ Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC, Khamashta MA, Shoenfeld Y (2003). "Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines". Lupus 12 (7): 530–4.  
  11. ^ Horton JD, Bushwick BM (1999). "Warfarin therapy: evolving strategies in anticoagulation". American Family Physician 59 (3): 635–46.  
  12. ^ de Jong PG, Goddijn M, Middeldorp S (2013). "Antithrombotic therapy for pregnancy loss". Human Reproduction Update 19 (6): 656–673.  
  13. ^ Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA (October 2010). "Antiphospholipid syndrome". Lancet 376 (9751): 1498–509.  
  14. ^ a b Hughes GR (October 1983). "Thrombosis, abortion, cerebral disease, and the lupus anticoagulant". Br. Med. J. (Clin Res Ed) 287 (6399): 1088–9.  
  15. ^ Sanna G, D'Cruz D, Cuadrado MJ (August 2006). "Cerebral manifestations in the antiphospholipid (Hughes) syndrome". Rheum. Dis. Clin. North Am. 32 (3): 465–90.  
  16. ^ Erkan D, Derksen R, Levy R, Machin S, Ortel T, Pierangeli S, Roubey R, Lockshin M (2011). "Antiphospholipid Syndrome Clinical Research Task Force Report". Lupus 20 (2): 219–224.  


  • Triona Holden (2003). Positive Options for Antiphospholipid Syndrome (APS): Self-Help and Treatment. Hunter House (CA).  
  • Kay Thackray (2003). Sticky Blood Explained. Braiswick. A personal account of dealing with the condition.  
  • Graham R V Hughes (2009). Understanding Hughes Syndrome: Case Studies for Patients. Springer. 50 case studies to help you work out whether you have it.  

External links

  • APS Foundation of America, Inc.
  • Hughes Syndrome Foundation
  • Interview with Hughes The Daily Telegraph February 2, 2009. Accessed February 3, 2009.
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