A previously fit and well 64 year old gentleman presented to the acute medical unit with a two-week history of lethargy, bruising, dark urine and an episode of transient facial numbness, blurred vision and dysarthria lasting 30 minutes. Clinical examination revealed mild jaundice, multiple bruises and a palpable liver edge but was otherwise normal. His respiratory rate was 14 breaths/minute with normal oxygen saturations. He was in sinus rhythm with a pulse of 68 beats/minute and non-invasive blood pressure was 130/70. He was GCS 15 and was apyrexial.
His full blood count revealed a haemoglobin of 94 g/L, platelets 9 x109/L, and white cell count 9 x109/L. A blood film showed red cell fragmentation, spherocytes, polychromasia, poikilocytosis and no platelet clumps. Reticulocytes and lactate dehydrogenase were raised at 168.6 x 109/L and 3027 iu/L respectively. Liver function tests revealed a bilirubin of 49 µmol/L but were otherwise normal. A liver ultrasound showed fatty infiltration. Clotting was normal and direct antiglobulin test negative. Urea and electrolytes were normal, creatinine 80 µmol/L and the C reactive protein was 37. ADAMTS13 assay showed complete absence of activity. CT brain was normal.
He was reviewed by the haematologists who diagnosed thrombotic thrombocytopenic purpura and referred him to the intensive care unit for plasma exchange. He received a three-day course of methylprednisolone, was intubated due to agitation, received plasma exchange with octaplas replacement that increased from 2 litre to 5 litre exchanges, and rituximab 750mg.
He deteriorated progressively with: vomiting, anaemia requiring blood transfusions, worsening thrombocytopenia, acute kidney injury with a peak creatinine of 457 µmol/L, an inferior ST elevation myocardial infarction, and a posterior cerebral artery territory infarct.
On day 5 he developed fixed and dilated pupils. Mannitol 1g/kg was administered and an urgent CT brain performed. This revealed multiple infarcts in both cerebral hemispheres and right cerebellum, loss of grey-white differentiation, 5mm midline shift and low cerebellar tonsils.
After discussion with the neurosurgeons it was decided this was an unrecoverable injury. In agreement with his family, end of life care was instituted and he died within 24 hours.
Describe the management of Thrombotic Thrombocytopaenic Purpura.
Sonya Daniel
Thrombotic thrombocytopenic purpura (TTP) is rare with an incidence of 6 cases per million per year in the United Kingdom. It has a mortality of 90% if left untreated. The classical description of TTP is of the pentad of fever, fluctuating neurological signs, renal failure, microangiopathic haemolytic anaemia (MAHA) and thrombocytopenia. The revised diagnostic criteria recognises that patients may not present with the full pentad of clinical features and so recommends that TTP should be considered in patients with MAHA and thrombocytopenia alone.1,2,3,4
TTP occurs due to a severe deficiency of a von Willebrand factor (vWF) cleaving protease known as ADAMTS13. When ADAMTS13 is absent vWF remains abnormally large and causes disseminated platelet aggregation. This occurs particularly in the microvasculature of the kidneys, brain, and heart. ADAMTS13 deficiency may be congenital or acquired. In the acquired form, deficiency is caused by autoantibodies produced against ADAMTS13.1,2,3,4
The most effective treatment for TTP is plasma exchange (PEx). Mortality rates have reduced to 10-20% since the advent of PEx in TTP. PEx removes autoantibodies and re-establishes ADAMTS13 activity. It is recommended that PEx should start with 1.5 times plasma volume exchanges. Daily exchanges should continue for at least two days after the platelet count is consistently above 150×109/L. Thereafter the exchange volume can be decreased to 1 times plasma volume. However, TTP resistant to treatment may need increased frequency or higher volume exchanges particularly if cardiac or neurological events occur.1,2,3
Normal ADAMTS13 activity is present in fresh frozen plasma (FFP), methylene blue treated FFP, psoralen treated FFP and solvent/detergent treated plasma. The department of health recommends the use of solvent/detergent treated plasma (e.g. octaplas) in the treatment of patients with TTP to reduce the incidence of adverse immune responses and transfusion related infection.1
Intravenous methylprednisolone 1gram/day for 3 days or oral prednisolone (1mg/kg/day) are commonly used in conjunction with PEx in the initial management of TTP. Corticosteroids are associated with improved outcomes.1,2,3
Rituximab, a monoclonal antibody against CD20 found on B cells, results in decreased ADAMTS13 autoantibodies, increased ADAMTS13 activity and reduces the rate of relapse. Indications for the use of rituximab include: treatment refractory TTP, relapsed TTP and neurological or cardiac involvement (which is associated with a higher mortality).1,2,3
Supportive treatments in TTP include blood transfusion, folic acid and thromboprophylaxis. Blood transfusion may be needed to correct anaemia, particularly in patients with cardiac involvement and haemolysis. Folic acid supplementation is necessary in haemolysis as it is consumed rapidly and causes megaloblastosis. Platelet transfusions are contraindicated as this may exacerbate thrombus formation but may be required in uncontrolled haemorrhage. Low dose aspirin and low molecular weight heparin are recommended when platelets are more than 50 x 109/L.
Lessons Learnt
Thrombotic thrombocytopenic purpura is a rare disorder that presents with a fulminant clinical course. Early recognition and prompt treatment with plasma exchange, steroids and rituximab in resistant disease is imperative to reduce mortality.
References
- Sully M, Hunt B, Benjamin S, Liesner R, Rose P, Peyvandi F, Cheung B, Machin S. Guidelines On The Diagnosis And Management Of Thrombotic Thrombocytopenic Purpura And Other Thrombotic Microangiopathies. British Journal Of Haematology 2012. Doi:10.111/j.1365-2141.2012.09167.x
- George J. Thrombotic Thrombocytopenic Purpura. N Engl J Med 2006; 354: 1927-1935.
- Rock GA. Review: Management Of Thrombotic Thrombocytopenic Purpura. British Journal Of Haematology 2000; 109: 496-507.
- Saifan C, Nasr R, Mehta S, Acharya PS, El-Sayegh S (2012) Thrombotic Thrombocytopenic Purpura. J Blood Disord Transfus S3:001. doi:10.4172/2155-9864.S3-001
ICM Case Summaries 