Microangiopathic antiphospholipid syndrome

T he occurrence of small-vessel occlusions (thrombotic microangiopathy) in association with anti-phospholipid antibodies (aPL) affecting, for example, the retinal vessels, the nail fold, 3 the skin, or major intrabdominal organs such as the kidney, the liver or the bowel, although uncommon, is well documented. These occlusions have been described in the simple or classic antiphospholipid syndrome (APS), whether or not associated with systemic lupus erythematosus (SLE), or in the primary APS, but they do not in any way dominate the clinical picture in these conditions. However, with the description and definition of the catastrophic APS (also known as Asherson’s syndrome) in 1992 8 (a new subset of the APS, often fatal, with many distinguishing characteristics separating it from the simple APS), there has been renewed interest in the thrombotic microangiopathies and their association with aPL. Although large-vessel occlusions do occur in catastrophic APS, they do not dominate the clinical picture, and their frequency is completely different from that encountered in the classic APS itself. Additionally, the catastrophic APS is frequently accompanied by a systemic inflammatory response syndrome (SIRS). The term thrombotic microangiopathic haemolytic anaemia (TMHA) was originally introduced by Symmers in 1952 to describe a clinical state with localised or diffuse microvascular thrombosis in association with haemolytic anaemia and fragmented red cells referred to as schistocytes. Indeed, the great haematologist John Dacie and his colleagues published a seminal paper on TMHA and related the condition to vascular damage some 10 years later. TMHA encompasses a spectrum of disorders including thrombotic thrombocytopenic purpura (TTP), haemolytic–uraemic syndrome (HUS), malignant hypertension, postpartum renal failure, pre-eclampsia and catastrophic APS. Recent articles still refer to the difficulty in distinguishing among these conditions 15 as the overlap is so great. With the advent of refined testing for aPL, many cases of TTP were published with this association, although Kincaid-Smith in 1988 had already pointed out the existence of renal thrombotic microangiopathy with lupus anticoagulant positivity. The next major advance in this field was the identification of the cleaving enzyme—a von Willebrand factor Disintegrin and Metalloproteinase ThromboSpondin protein (ADAMTS–13). Three patients with TTP and aPL have been reported so far. 24 Espinosa et al in 2005 reviewed the association of aPL with TMHA comprehensively and found an association of TMHA with catastrophic APS rather than with classic APS. The association of HUS with aPL has also been anecdotically documented. Simultaneous with the TTP and aPL story came the association of patients with the haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome and aPL. Hepatic infarctions, retinal vascular occlusions and deep venous thrombosis (DVT) 39 have now been reported in patients with HELLP syndrome. Three recent papers have speculated as to whether a continuum exists between several of these conditions (TTP, HUS, HELLP syndrome and catastrophic APS). This has been prompted by the reports of TTP and HELLP syndrome in patients in whom aPL has been demonstrated and alluded to above and also by recent case reports of patients with HELLP syndrome and catastrophic APS. 44 To these conditions must also be added disseminated intravascular coagulation (DIC), another situation where microvascular thromboses may be seen because of the hypercoagulability, and this may often be accompanied by a haemorrhagic state. There is usually strongly enhanced inflammatory activity, activated coagulation and impaired fibrinolysis in DIC, with a major role proposed for granulocytes. 46 Its frequency in catastrophic APS has also been highlighted recently, and there have also been studies pointing out the frequency of positive aPL demonstrated in DIC itself. Indeed, the index case for catastrophic APS demonstrated serological evidence of DIC. It should be stressed, however, that TTP, HUS, HELLP and DIC display abnormalities in the coagulation that are not usually associated with classic APS and are responsive to treatment regimens not effective in APS. It is therefore time to address this topic objectively and to evaluate whether indeed there is a case to be made for another separate ‘‘subset’’ of the APS— namely, a microangiopathic APS. The primary APS 50 and the catastrophic APS have certainly stood the test of time as unique conditions in the APS spectrum. We now know that patients with primary APS may develop SLE with time, and also that .80% of patients with catastrophic APS have a history of simple APS. What is the role of the aPL (if any) in these microangiopathic conditions? Are they truly pathogenic, or are they simply ‘‘bystanders’’ induced by endothelial cell activation/apoptosis and exposure of phospholipid on the endothelial cell membranes of small vessels? In these conditions—for example, in TTP itself (apart from 20–30% of patients with catastrophic APS)—there are no large vascular occlusions. Hence, their relationship with the APS itself, with predominantly large-vessel occlusions, is distant, although a minority of patients with TTP demonstrate features of APS and the vast majority of patients with HELLP do not demonstrate larger vascular occlusions. The first major player in this scenario must be the endothelial cells themselves and, in particular, those vascular endothelial cells present only on small vessels. The pathogenesis of the vascular occlusions affecting larger vessels causing DVT and strokes must then surely be different. The multifactorial pathogenesis of the APS has recently been well reviewed by Mackworth-Young. The second major player in this scenario is the complement cascade, and both their roles will be briefly summarised here.