a) Outline the pathophysiology, clinical and diagnostic features of Thrombotic Thrombocytopenic Purpura (TTP). (70% marks)
b) Outline the specific management of TTP. (30% marks)
Pathophysiology (2 marks)
Severe deficient activity of ADAMTS13 protease resulting in ultralarge von Williebrand factor (VWF) multimers to accumulate on the endothelial surface causing platelet aggregation and clumping with microthrombi formation leading to microangiopathic haemolytic anaemia (MAHA) and organ dysfunction. ADAMTS13 deficiency usually acquired (inhibitory autoantibody) or hereditary (inherited ADAMTS13 mutation). Enzyme activity is reduced during sepsis, pancreatitis, liver disease, pregnancy (2nd and 3rd trimester)
Clinical and diagnostic features (5 marks)
May present with weakness, fatigue, dyspnoea, gastrointestinal symptoms (abdominal pain/nausea/vomiting), history of bruising or bleeding with clinical findings of a petechial rash
Neurological symptoms (headache, confusion, seizure, stroke, coma)
Acute Kidney Injury (more likely in Haemolytic Uremic Syndrome)
FBC and peripheral smear – anaemia, thrombocytopenia Features of MAHA (schistocytes, spherocytes, polychromasia)
Haemolysis - markedly elevated LDH, elevated indirect bilirubin, reduced haptoglobins, negative Coombs testing
Severe ADAMTS13 deficiency
Renal parameters – urea and creatinine may be deranged
Specific Management (3 marks):
Daily exchanges 1.5 times plasma volume until remission. Replacement with cryodepleted plasma or FFP. (Replacement with 4% albumin would be inappropriate.)
Corticosteroids – reduce production of the ADAMTS13 inhibitor (autoantibody), reduced cytokine production or decreased autoantibody-mediated clearance of ADAMTS13.
Rituximab– chimeric monoclonal antibody directed against CD20 (found on B cells) –immunosuppressive
TTP is much beloved by the examiners, and will continue to appear in the papers. The superb pass rate for this SAQ (80.7%) demonstrates that the trainees recognise this.
Pathophysiology of TTP
From the college answer to Question 21 from the first paper of 2013:
"A trigger such as infection, surgery, pancreatitis, pregnancy, produces endothelial activation. ADAMTS 13 is a von Willebrand factor cleaving protein. When endothelial activation occurs and ADAMTS 13 activity is low (often due to an autoantibody inhibitor), large vWF multimers accumulate causing microvascular thrombosis and haemolys
Characteristic clinical features of TTP from Scully et al (2008)
Specific management of TTP (2012 British guidelines):
George, James N. "Thrombotic thrombocytopenic purpura." New England Journal of Medicine 354.18 (2006): 1927-1935.
Peyvandi, Flora, et al. "von Willebrand factor cleaving protease (ADAMTS‐13) and ADAMTS‐13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura." British journal of haematology 127.4 (2004): 433-439.
Tsai, Han-Mou. "Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura." Journal of the American Society of Nephrology 14.4 (2003): 1072-1081.
Oh's Intensive Care manual: Chapter 97 (pp. 993) Therapeutic plasma exchange and intravenous immunoglobulin therapy by Ian Kerridge, David Collins and James P Isbister
Kakishita, Eizo. "Pathophysiology and treatment of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS)."International journal of hematology 71.4 (2000): 320-327.
Noris, Marina, and Giuseppe Remuzzi. "Hemolytic uremic syndrome." Journal of the American Society of Nephrology 16.4 (2005): 1035-1050.
Kappler, Shane, Sarah Ronan-Bentle, and Autumn Graham. "Thrombotic Microangiopathies (TTP, HUS, HELLP)." Emergency Medicine Clinics of North America (2014).
Moake, Joel L. http://www.danielyoung.net/articles/NEJM%20TTP-HUS%202002.pdf "Thrombotic microangiopathies." New England Journal of Medicine 347.8 (2002): 589-600.
Page, Evaren E., et al. "Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015." Blood advances 1.10 (2017): 590-600.
Scully, Marie, et al. "Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features." British journal of haematology 142.5 (2008): 819-826.
Blombery, P., et al. "Diagnosis and management of thrombotic thrombocytopenic purpura (TTP) in Australia: findings from the first 5 years of the Australian TTP/thrombotic microangiopathy registry." Internal medicine journal 46.1 (2016): 71-79.
Scully, Marie, et al. "Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies." British journal of haematology 158.3 (2012): 323-335.