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Explore This IssueFebruary 2014
In April 2007, Graham R.V. Hughes, MD, wrote an article in The Rheumatologist titled, “Put Hughes Syndrome on Your Radar,” about this fascinating, relatively new disease called antiphospholipid syndrome (APS) that he had described some three decades earlier with Aziz Gharavi, MD, and E. Nigel Harris, MPhil, MD, DM.1 As clinical manifestations of APS increasingly are uncovered, every specialty in medicine must put this disease on its radar.
In the original description of APS, it was observed that, among patients suffering from systemic lupus erythematosus (SLE), there was an association between the presence of circulating antiphospholipid antibodies (aPLs) and thrombosis, pregnancy loss, and thrombocytopenia.2 Several years later, it became clear that APS can occur in the absence of an underlying systemic autoimmune disease (primary APS).3,4
A long list of clinical manifestations has been reported in APS affecting all organs, though some manifestations are less evident than others and require a high index of suspicion in order to make the diagnosis of APS.5
The manifestations of APS can be summarized by the presence of thrombotic events, pregnancy morbidity, and the detection of circulating aPLs. Both arterial and venous thrombosis can occur in APS. These can present with recurrent deep vein thrombosis; thrombosis of the internal organ vasculature such as the kidney, liver, lung, or brain; stroke or transient ischemic attacks; limb ischemia; or infarction of internal organs.6 The pregnancy morbidity is defined by either unexplainable death of a healthy fetus after 10 weeks’ gestation, premature birth of a healthy baby before 34 weeks’ gestation, or three or more consecutive unexplainable miscarriages before 10 weeks’ gestation.6
Some clinical manifestations are of particular interest, such as livedo reticularis. This is not only an important marker for APS, but is considered a risk factor for arterial thrombosis.7
Diffuse small-vessel thrombosis in multiple organ systems is a manifestation of catastrophic antiphospholipid syndrome, which is characterized by multi-organ failure and a mortality rate exceeding 50%.8
Several criteria for the classification of APS have been developed in parallel with a better understanding of its pathogenesis. The last revision of the APS criteria requires the patient to meet at least one clinical criterion and one laboratory criterion.
The clinical manifestations focused on vascular thrombosis and obstetric complications, while the lab criteria required the presence of either lupus anticoagulant (LAC), anticardiolipin (aCL), or anti–β2 glycoprotein–I antibodies (anti-β2GPI) on two occasions 12 weeks apart.9
Seronegative APS was first described in 2003. This group consisted of patients with typical clinical manifestations of APS, including arterial thrombosis, thrombocytopenia, heart valve lesions, and recurrent pregnancy loss, but with negative tests for LAC, aCL, and anti-β2GPI antibodies.10,11 Ongoing research has revealed the existence of other lipid-binding antibodies, including those targeting phosphatidylethanolamine, phospholipid-binding plasma proteins, phospholipid-protein complexes, and anionic phospholipids other than cardiolipin, which may induce thrombosis.12 The clinical relevance of these “non-criteria” is being debated. Their relevance will need confirmation by larger longitudinal studies.
Pathogenesis of APS
Multiple pathways are implicated in the pathogenesis and thrombus formation in APS, including cellular effects (on platelet membranes, endothelial cells, and monocytes), plasma coagulation regulatory proteins (clotting components such as prothrombin, protein C, and protein S), and fibrinolysis.13