Advances in thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura is an acute life-threatening condition with a high mortality rate. Here, consultant haematologist Professor Marie Scully MBE explains how recent advances in its treatment and management have improved the outcomes for patients with this condition.

Thrombotic thrombocytopenic purpura (TTP) is life-threatening and a medical emergency. It presents rapidly around 40 years of age and is more common in females. Without treatment, the mortality rate is over 90%. Around 90% of cases are due to patients forming antibodies to the metalloprotease enzyme ADAMTS 13 – this is known as immune TTP. The other 10% of cases have a genetic cause (hereditary deficiency of ADAMTS 13) known as congenital TTP.

Thrombotic thrombocytopenic purpura is a medical emergency … Without treatment, the mortality rate is over 90%.

ADAMTS 13 is a protein that plays an essential role in the regulation of blood clotting by cleavage of von Willebrand factor (VWF) with splitting of ultra-large VWF multimers into smaller VWF multimers. In TTP, there is a deficiency of ADAMTS 13, resulting in the accumulation of ultra-large VWF multimers, which have increased platelet binding. This results in microvascular thrombosis with blockage of small blood vessels and end organ damage.

Clinically, the presentation of TTP may be heterogeneous (diverse) but it is usually associated with low levels of blood platelets (thrombocytopenia) and microangiopathic haemolytic anaemia (a type of anaemia resulting from damage to red blood cells when blood vessels are blocked).

Mark’s story

Mark, a 45-year-old male of Afro-Caribbean heritage, presented on a Saturday night with vomiting, confusion and a rapid decrease in his Glasgow Coma Scale (GCS) that measures the level of consciousness in a patient. He required admission to the intensive care unit (ICU) following intubation and ventilation. He was transferred for urgent plasma exchange (PEX) following a presumed diagnosis of TTP. In PEX, diseased plasma is separated and removed from the blood and replaced with donor plasma. A blood film confirmed thrombocytopenia, fragmented red blood cells and polychromasia (the latter indicating a high number of immature red blood cells in the bloodstream seen in haemolytic anaemia). A diagnosis of TTP was confirmed through analysis of ADAMTS 13 activity levels, which were severely reduced, and antibodies to ADAMTS 13, which were very high.

Mark’s presentation was severe and his prognosis was poor even with treatment.

Mark’s presentation was severe and his prognosis was poor even with treatment. He had neurological involvement with confusion and reduced GCS on admission and raised levels of troponin – a protein released into the bloodstream when the heart muscle is damaged.

Mark received PEX immediately on transfer and intravenous methylprednisolone, a drug used to treat inflammation and immune reactions in various organs. Before his second PEX on the day of admission and following confirmation of severe ADAMTS 13 deficiency, Mark was started on caplacizumab (an antibody fragment that targets VWF, preventing it from binding to platelets and causing blockages), which he then received daily. As well as receiving daily PEX until his platelet count had increased, Mark started rituximab on day 2 of admission and oral prednisolone. Both rituximab and prednisolone inhibit the production of anti-ADAMTS 13 antibodies, thus increasing ADAMTS 13 activity. Mark was extubated within 48 hours and discharged with continued treatment as an outpatient on day 8.

Advances in TTP care

Mark’s case highlights several achievements in TTP care. Firstly, prompt diagnosis using blood film analysis and the testing of LDH levels as useful tools allowing rapid initiation of treatment.

The identification of the immune basis of thrombotic thrombocytopenic purpura has resulted in the introduction of appropriate immunosuppressive treatment that reduces the time patients spend in hospital receiving treatment.

Secondly, the identification of the immune basis of TTP has resulted in the introduction of appropriate immunosuppressive treatment that reduces the time patients spend in hospital. For example, rituximab shortens the time to remission and inpatient care to a median of 14 days or 21 days if admitted to ICU. Finally, the introduction of the novel anti-VWF antibody caplacizumab into the patient treatment pathway results in quicker normalisation of the platelet count and reduces the number of PEX procedures required and days in hospital.1 Mark’s case exemplifies this.

What is the future for Mark?

TTP is a chronic condition that requires lifelong follow up. There is a 30–50% risk of relapse, which can be averted by monitoring ADAMTS 13 activity levels in an out-patient setting. When the levels drop from normal (complete remission) to 15–20% (ADAMTS 13 relapse), despite normal routine laboratory parameters, further treatment with rituximab is given to normalise ADAMTS 13 activity levels and re-achieve complete remission. The treatment pathway in acute TTP and the long-term monitoring of this condition have resulted in a significant decrease in mortality, preventing the likelihood of the condition worsening, failing to respond to treatment and relapse. The recent commissioning of regional TTP centres in England will enable equity of care and improve national outcomes in this rare but devastating condition.

References available