Concurrent thrombotic thrombocytopenic purpura and antiphospholipid syndrome: a rare and severe clinical combination

Thrombotic Thrombocytopenic Purpura (TTP) and Antiphospholipid Syndrome (APS) are two well-differentiated processes. TTP is an infrequent disease characterized by microangiopathic haemolytic anaemia, thrombocytopenia, neurological manifestations and renal failure. The occlusion of the microvessels by microthrombi, mainly composed of platelets, constitutes the basic lesion of this condition. It is apparently a consequence of the unusually large von Willebrand factor multimers, due to congenital ADAMTS13 deficiency or the presence of anti ADAMTS13 (Moake et al, 1982). In contrast, APS constitutes a frequently diagnosed syndrome, characterized by recurrent thrombosis, obstetrical morbidity and the presence of antiphospholipid (aPL) antibodies. An unusual clinical APS presentation, called Catastrophic APS, consists of multi-organ failure secondary to a thrombosis, involving both large vessels and microcirculation, thrombocytopenia and microangiopathic anaemia and could make a differential diagnosis with TTP difficult (Asherson et al, 2003). Antiphospholipid syndrome can be primary or associated with other autoimmune diseases, but a clinical association of APS and TTP has been rarely described. In most patients, the diagnosis was established only on the basis of clinical criteria (Espinosa et al, 2004). Paradoxically, a high prevalence of anti ADAMTS13 antibodies and/or ADAMTS13 dysfunction in patients with APS or aPL antibodies has been reported (Austin et al, 2008), although without clinical significance. Despite these findings, we describe here a case of apparent APS and TTP association. A 49-year-old woman with a Lupus Anticoagulant (LA), but without a prior clinical history of thrombosis or miscarriage despite having had five children and several surgical procedures, developed recurrent arterial brain thrombosis, followed in a very short period of time by severe TTP with very low levels of ADAMTS 13 and high levels of anti ADAMTS 13 antibodies. Initially, the patient was referred to the Haematology Department in June 2006 for mild anaemia: haemoglobin 114 g/l, thrombocytopenia 63 · 10/l and a prolonged activated partial thromboplastin time (APTT). Iron, vitamin B12 and Folic acid levels were normal, and there were no haemolytic data. The APTT was 52 s (normal control: 30 s), which was not corrected when mixed with normal plasma. Because of her good general state, she was scheduled for a further study of probable LA. However, 2 months later (August 2006) the patient presented at the emergency room with a sudden episode of right side hemiparesis. The computed tomography scan was normal, and with a diagnosis of suspected atherothrombotic brain stroke, the patient was hospitalized and started on a treatment of aspirin, 300 mg/d. At that time the laboratory tests showed haemoglobin 109 g/l, platelet count 43 · 10/l and APTT 52 s. In the following days, the platelet count decreased to 17 · 10/l, but without changes in the other haematological parameters. Uric acid was 0Æ45 lmol/l, total bilirubin 23Æ9 lmol/l; lactic dehydrogenase (LDH) levels were normal. The investigation of LA using APTT LA time and the diluted Russell Viper Venom Test (Instrumentation Laboratory, Lexington, MA, USA) was positive: APTT-LA: 86Æ7 s APTTLA ratio: 2Æ41, dilute viper venom (DVV) test: 56Æ8 s, DVV test ratio: 1Æ43 (positive >1Æ21). Anti-Beta2 Glycoprotein1 IgG and IgM antibodies (Aesku Diagnostics, Waldesheim, Germany) were 18Æ3 and 1Æ3 U/ml, respectively. Antinuclear antibodies (titre, 1:640), anti-ribonucleoprotein and antihistone antibodies were positive, but Systemic Lupus was discarded because of the absence of other criteria. Initially diagnosed as an Immune Thrombocytopenic Purpura associated with APS, the patient was treated with corticosteroids and a high dose of immunoglobulins without response. Fourteen days after her latest presentation, the patients neurological condition worsened. A cranial magnetic resonance imaging scan showed a sub-acute ischemic infarction in the left parietal region. Laboratory tests were haemoglobin of 82 g/l, platelet count 11 · 10/l and an increased LDH of 737 iu per ml. Two days later schistocytes were observed in blood smears. Her platelet count had fallen to 4 · 10/l and the serum haptoglobin was undetectable. ADAMTS13 levels were 48Æ2 lg/l (normal >208Æ7 lg/l) and anti ADAMTS13 antibodies 46Æ9 AU/ml (normal <12Æ74 AU/mL) (Inmubind ; American Diagnostica, Greenwich, CT, USA). With the definitive diagnosis of TTP associated with an APS, the patient was started on a combined treatment of daily plasmatic exchange with fresh frozen plasma, plasma transfusion every 6 h and a weekly dose of Rituximab (375 mg/m). The patient received a total of 18 plasmaphereses and four Rituximab doses. A progressive response occurred, with a complete neurological and haematological recovery. As soon it was possible, an oral anticoagulation with acenocoumarol was started. Two years later, the patient remained asymptomatic, with platelet counts over 150 · 10/l, normal ADAMTS13 levels and absence of anti ADAMTS13 antibodies. The patient is currently under permanent anticoagulation with dicumarin. Correspondence