Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies

Abstract

The guideline group was selected to be representative of UK-based medical experts. MEDLINE and EMBASE were searched systematically for publications in English, using the keywords: thrombotic thrombocytopenia purpura (TTP), ADAMTS13, plasma exchange (PEX) and relevant key words related to the subsections of this guideline. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the BCSH. The guideline was then reviewed by a sounding board of British haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The 'GRADE' system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com. The objective of this guideline is to provide healthcare professionals with clear, up-to-date, and practical guidance on the management of TTP and related thrombotic microangiopathies, defined by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and small vessel thrombosis. Thrombotic thrombocytopenic purpura (TTP) is rare, with a reported incidence of six cases per million per year in the UK (Scully et al, 2008). It is an important diagnosis to make because the untreated mortality is 90%, which can be reduced with the prompt delivery of plasma exchange (PEX). Early death still occurs: approximately half of the deaths in the regional UK registry occurred within 24 h of presentation, primarily in women (Scully et al, 2008). In the last 15 years there has been a marked increase in the understanding of the pathogenesis of TTP. It is now recognized that congenital and acute acquired TTP are due to a deficiency of von Willebrand factor (VWF) cleaving protein, also known as ADAMTS1, (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 – von Willebrand factor cleaving protein) (Fujikawa et al, 2001; Levy et al, 2001). In the absence of ADAMTS13, ultra large multimers of VWF (ULVWF) released from endothelium are not cleaved appropriately, and cause spontaneous platelet aggregates in conditions of high shear, such as in the microvasculature of the brain, heart and kidneys. Congenital TTP is due to an inherited deficiency of ADAMTS13, but acquired immune TTP is due to the reduction of ADAMTS13 by autoantibodies directed against ADAMTS13 (Furlan et al, 1998a; Tsai & Lian, 1998). Other clinical forms of thrombotic microangiopathy (TMA) occur in the absence of severe deficiency. Diagnosis can be difficult, as there is clinical overlap with haemolytic uraemic syndrome (HUS), autoimmune disease and a spectrum of pregnancy-related problems. Thrombotic thrombocytopenic purpura was originally characterized by a pentad of thrombocytopenia, MAHA, fluctuating neurological signs, renal impairment and fever, often with insidious onset. However, TTP can present without the full pentad; up to 35% of patients do not have neurological signs at presentation and renal abnormalities and fever are not prominent features. The revised diagnostic criteria state that TTP must be considered in the presence of thrombocytopenia and MAHA alone (Galbusera et al, 2006). This can result in an increased referral of other TMAs (Table 1). TTP remains a diagnosis based on clinical history, examination of the patient and the blood film. ADAMTS 13 assays help to confirm the diagnosis and monitor the course of the disease and possible need for additional treatments. Presenting symptoms and signs are summarized in Table 2 and reflect widespread multi organ thromboses. Neurological impairment has multiple presentations including headache, altered personality, reduced cognition, transient ischaemic attacks, fits and fluctuating levels of consciousness including coma; the latter is a poor prognostic sign. Acute renal failure requiring haemodialysis is rare in TTP and more indicative of HUS (Coppo et al, 2006; Scully et al, 2008). Additional ischaemic complications may be seen, such as abdominal pain due to intestinal ischaemia. Consumption of platelets in platelet-rich thrombi results in thrombocytopenia. The median platelet count is typically 10–30 × 109/l at presentation (Dervenoulas et al, 2000; Vesely et al, 2003; Coppo et al, 2006; Tuncer et al, 2007; Scully et al, 2008). Mechanical fragmentation of erythrocytes during flow through partially occluded, high shear small vessels causes a MAHA. Median haemoglobin levels on admission are typically 80–100 g/l, with schistocytes in the film, low haptoglobin levels and raised reticulocyte counts due to haemolysis. The direct Coombs test is negative. The combination of haemolysis and tissue ischaemia produces elevated lactate dehydrogenase (LDH) values. The clotting screen (prothrombin time, activated partial thromboplastin time and fibrinogen) is usually normal. A virology screen pre-treatment is necessary to exclude human immunodeficency virus (HIV) and other viral-associated TTP, and a