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Antiphospholipid Syndrome: Overview, Diagnosis, and Treatment

About Antiphospholipid Syndrome (APS)

Antiphospholipid syndrome (APS) is an emerging condition that may underlie more conditions than first perceived. The diverse symptoms of APS include deep venous thrombosis of lower limbs, pulmonary embolism, early and late miscarriages, memory impairment, clinical features of arthritis, livedo reticularis, migraine, or epilepsy.1,2 It is a systemic autoimmune disease in which antibodies are directed against phospholipid-protein complexes.3

APS is more common in women than men in about a 5:1 ratio. Although the mean onset age of clinical manifestations tends to occur in the middle-age range, it may manifest in children and older patients as well. APS appears to lead directly to a combination of symptoms. Headaches—particularly migraines—going back to childhood and often with family history can be an early feature of APS.2

Recognizing the following clinical manifestations is an important step toward an earlier diagnosis:4

  • Thrombocytopenia (30%)
  • Livedo reticularis (24%)
  • Heart valve lesions (12%)
  • Hemolytic anemia (10%)
  • Epilepsy (7%)
  • Myocardial infarction (6%)
  • Leg ulcers (6%)
  • Amaurosis fugax (5%)

5:1 Ratio

Antiphospholipid syndrome is more common in women than men.

The diverse symptoms of APS include:1,2

  • Deep venous thrombosis of lower limbs
  • Pulmonary embolism
  • Early and late miscarriages
  • Memory impairment
  • Clinical features of arthritis
  • Livedo reticularis
  • Migraine
  • Epilepsy

Some symptoms that should prompt you to consider diagnostic testing for APS include heart valve lesions, headaches, epilepsy, livedo reticularis, and other autoimmune conditions.3

Antiphospholipid syndrome: Refining differential diagnosis through testing

Currently there are no clinical guidelines for the diagnosis of APS; the only available guidance is the classification criteria, which are primarily intended for clinical research. The classification criteria for APS require the identification of at least one clinical and one laboratory criterion.3

 

Clinical criteria for APS classification

Vascular thrombosis. One or more clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ. Thrombosis must be confirmed by objective validated criteria. For histopathological confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall.

Pregnancy morbidity. One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, OR one or more premature births of a morphologically normal neonate before the 34th week of gestation because of:

  • Eclampsia or severe pre-eclampsia, or
  • Recognized features of placenta insufficiency
  • Three or more unexplained, consecutive, spontaneous abortions before the 10th week of gestation

While thrombosis and fetal and obstetric complications are the most recognizable clinical signs of APS, and included in the classification criteria, there is growing evidence of APS presenting with other symptoms.

Some symptoms that should prompt you to consider diagnostic testing for APS include heart valve lesions, headaches, epilepsy, livedo reticularis, and other autoimmune conditions.3

 

Laboratory criteria for APS classification

The hallmark serological testing result that defines APS is the presence of persistent antiphospholipid antibodies (aPL). To be classified as APS, international consensus of the classification criteria state that a patient must have elevated titers of one of the following antiphospholipid antibody (aPL):3,5

  • Lupus anticoagulant in plasma
  • Anticardiolipin antibodies (IgG and/or IgM), considered elevated medium or high titer (>40 GPL or MPL or > 99th percentile) in serum or plasma
  • Anti-β2-glycoprotein I antibodies (IgG and/or IgM), considered elevated titers a titer > 99th percentile in serum or plasma

These antiphospholipid antibodies are considered to be diagnostic markers and pathogenic drivers of APS.6 The classification criteria for APS states a patient who fulfills clinical criteria can be classified as APS dependent when the patient exhibits a persistently positive aPL result on two or more occasions at least 12 weeks apart.3,7

 

 

Not sure which allergy or autoimmune disease could be behind your patient’s symptoms? Use this interactive tool to take the next step in making your differential diagnosis. 

Venous and arterial thromboses: The hallmarks of APS1,4

Deep vein thrombosis, sometimes accompanied by pulmonary embolism, is the most frequently reported manifestation in this syndrome (about 39 percent). Cerebrovascular accidents—either stroke (20 percent) or transient ischemic attacks (11 percent)—are the most common arterial thrombotic manifestations.

 

Fetal and obstetric manifestations of APS are also common with:8

  • Prematurity (28%)
  • Early pregnancy loss (18%)
  • Pre-eclampsia (up to 8%)

Testing Confidence

Testing Increases Diagnostic Confidence

Adding diagnostic testing to aid in a differential diagnosis has been shown to increase confidence in diagnosis to 90 percent.i,ii Conventionally, a diagnosis of allergic or autoimmune disease relies on the case history and a physical examination. However, adding diagnostic testing to aid in a differential diagnosis has been shown to increase confidence in diagnosis.i,ii Diagnostic testing can also help to improve the patient’s quality of life and productivity, reduce costs associated with absenteeism, and optimize use of medication, in addition to decreasing unscheduled healthcare visits.iii,iv 

i. Duran-Tauleria E, Vignati G, Guedan MJ, et al. The utility of specific immunoglobulin E measurements in primary care. Allergy. 2004;59 (Suppl78):35-41.
ii. NiggemannB, Nilsson M, Friedrichs F. Paediatric allergy diagnosis in primary care is improved by in vitro allergen specific IgE testing. Pediatr Allergy Immunol. 2008;19:325-331
iii. Welsh N, et al. The Benefits of Specific Immunoglobulin E Testing in the Primary Care Setting. J Am Pharm Assoc. 2006;46:627.
iv. Szeinbach SL, Williams B, Muntendam P, et al. Identification of allergic disease among users of antihistamines. J Manag Care Pharm. 2004; 10 (3): 234-238

Learn about autoimmune disease.

Learn more about testing.

Management and care of patients with antiphospholipid syndrome    

Antiphospholipid syndrome (APS) is an acquired autoimmune condition that affects young patients, primarily women, in the most productive years of their lives, and the consequences of organic or tissue damage involve a decrease in health-related quality of life (HRQoL).9

APS is under-recognized and underdiagnosed and can have devastating results if untreated, mainly due to uncontrolled thrombosis. Treatment can reduce mortality and morbidity in young people who often present with stroke, myocardial infarction, and deep vein thrombosis.10

There are no clinical practice guidelines covering all aspects of the diagnosis and treatment of APS; the available guidance is the classification criteria that are primarily intended for clinical research. The classification criteria for APS require the identification of at least one clinical and one laboratory criterion.10

With no formal clinical guidelines in place in the United States, diagnosis and treatment of APS is largely based on consensus and expert opinion.11

Practice Parameters

Practice parameters and guidelines

for antiphospholipid syndrome:

References
  1. Sciascia S, Baldovino S, Schreiber K, et al. Thrombotic risk assessment in antiphospholipid syndrome: the role of new antibody specificities and thrombin generation assay. Clin Mol Allergy. 2016:14:6. 
  2. Hughes RV. Put Hughes Syndrome on Your Radar. The Rhematologist. 2007. http://www.the-rheumatologist.org/article/put-hughes-syndrome-on-your-radar/. Accessed November 2017.
  3. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295-306.
  4. Asherson RA, Cervera R. The antiphospholipid syndrome: multiple faces beyond the classical presentation. Autoimmun Rev. 2003;2:140-151.
  5. Marchetti T, Cohen M, de Moerloose P. Obstetrical Antiphospholipid Syndrome: From the Pathogenesis to the Clinical and Therapeutic Implications. Clin Develop Immuno. 2013; Article ID 159124.
  6. Pericleous C, Ripoll VM, Giles I, et al. Laboratory tests for the antiphospholipid syndrome. Methods Mol Biol. 2014;1134:221-235.
  7. Devreese KMJ, Pierangeli SS, de Laat B, et al. Testing for Antiphospholipid Antibodies with Solid Phase Assays: guidance from the SSC of the ISTH.  J Thromb Haemost. 2014;12:792-795.
  8. Ortel TL. Antiphospholipid Syndrome Laboratory Testing and Diagnostic Strategies. Am J Hematol. 2012;87(Suppl 1):S75-S81.
  9. Alba P et al. Organ Damage and Quality of Life in Antiphospholipid Syndrome. Curr Rheumatol Rep. 2016. 18:7.
  10. Cohen D et al. Diagnosis and management of the antiphospholipid syndrome. BMJ. 2010 May 14;340:c2541.
  11. Limper M, Scirè CA, Talarico R, et al. Antiphospholipid syndrome: state of the art on clinical practice guidelines RMD Open. 2018;4:e000785