Question 17

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

Clinical features

Fever

Neurological symptoms (headache, confusion, seizure, stroke, coma)

Acute Kidney Injury (more likely in Haemolytic Uremic Syndrome)

Diagnostic features:

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):

Plasma exchange:

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

Discussion

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) 

• Neurological abnormalities in 78% of cases:
  • Coma (10% require invasive ventilation)
  • Headache
  • Encephalopathy
  • Stroke, transient ischaemic attack
• Temperature greater than 37·5°CS
• Non‐specific symptoms: fatigue, arthralgia or myalgia
• Gastroenterological features
  • Diarrhoea
  • Jaundice
• Cardiac symptoms
  • Chest pain, shortness of breath, ECG changes
• Symptomatic thrombocytopenia (petechiae, bruising, haematuria, menorrhagia)
• Renal manifestations (oliguria, haematuria, fluid overload)

Diagnostic features:

• MAHA- like blood film features fragmented red cells and other evidence of haemolysis:
  • Negative Coombs test (haemolysis is mechanical)
  • Elevated LDH
  • Low haptoglobin
  • Elevated bilirubin with a low conjugated fraction
  • Free haemoglobin in the blood
• Thrombocytopenia (obviously) 
• Renal failure: raised urea and creatinine

Specific management of TTP (2012 British guidelines):

• Start plasma exchange: three daily sessions of .5 volumes, then 1 volume per day until resolution of clinical features.
• Continue plasma exchanges until 2 days after the platelet count is in excess of 150
• Immediately after plasma exchange, commence high dose steroids: 1g/day of methylprednisolone for 3 days, or oral prednisolone 1mg/kg/day
• Also:
  • give folic acid 5mg/day
  • Ensure PPI is added
• If there is neurological or cardiac involvement, commence Rituximab
• Don't transfuse any more platelets unless strongly indicated
• Once platelets increase to over 50, one may start s/c heparin and oral aspirin