Thrombotic thrombocytopenic purpura (TTP) is a rare but often fatal disease with an estimated incidence of 3.7 cases per one million people. TTP was initially described by Moschcowitz in 1924  and is characterised by the systemic microvascular aggregation of platelets causing ischaemia of the brain and other organs . A pentad of signs and symptoms has been described: thrombocytopenia, microangiopathic haemolytic anaemia, neurological abnormalities, renal failure and fever . Platelet counts are often below 20 × 109 l−1 due to the systemic clumping of platelets. Without treatment the mortality rate is greater than 90%, but this falls to 10–20% with plasma exchange and other therapies. Thrombotic microangiopathies with severe organ dysfunction leading to hospitalisation on the intensive care unit are associated with higher mortality rates .
Thrombotic thrombocytopenic purpura (TTP) is characterised by the systemic microvascular aggregation of platelets causing ischaemia of the brain and other organs. We describe the case of a 54 year-old man who presented with neurological signs, fever, severe thrombocytopenia, microangiopathic haemolytic anaemia and renal failure 5 days after receiving an influenza vaccination. He was diagnosed with acute refractory TTP caused by autoantibody-mediated ADAMTS-13 deficiency. He required stabilisation on the critical care unit before being successfully treated with 3 l plasma exchanges for 21 days and rituximab (MabThera®) at a dose of 375 mg.m−2, given weekly for a total of 4 weeks. Vaccination is an important part of preventative medicine and reduces morbidity and mortality. Only in a few rare cases has vaccination been associated with autoimmune pathology. We could find only one similar case report of thrombotic thrombocytopenic purpura following influenza vaccination. In addition to plasma exchange, rituximab appears to be effective and well tolerated in the treatment of refractory thrombotic thrombocytopenic purpura.
A 54 year old Afro-Caribbean man presented with agitation and confusion. This had been preceded by 24-h of malaise, fevers and non-specific headache. His background medical history included type II diabetes mellitus (insulin treated), hypertension and a previous myocardial infarction. Current treatment was human mixtard insulin, lisinopril, aspirin and simvastatin. There had been no recent changes to his medication, no history of weight loss and he had been married for over 30 years. Five days prior to admission he was vaccinated against influenza with a commercial vaccine (inactivated influenza vaccine (split virion) BP (Sanofi Pasteur MSD)) as part of a routine vaccination programme.
On admission he was extremely agitated, pulse 115 beat.min−1 and blood pressure 118/62 mmHg. He was noted to have bilateral subconjunctival haemorrhages, but no obvious rash or lymphadenopathy. The rest of the physical examination was unremarkable. Investigations performed on admission are summarised in Table 1. Serum samples for immunological analysis were sent after the first plasma exchange.
|Haemoglobin||5.7 g.dl−1||(12.5–16.5 g.dl−1)|
|White cell count||8.7 × 109 l−1||(4–11 × 109 l−1)|
|Platelets||7 × 109 l−1||(150–450 × 109 l−1)|
|International normalised ratio||1.1|
|D-dimers||6258 ng.ml−1||(0–210 ng.ml−1)|
|Fibrinogen||3.8 g.l−1||(1.5–4.5 g.l−1)|
|Blood film||Fragmented red cells; nucleated red cells|
|Urea||13.4 mmol.l−1||(1.0– 7.0 mmol.l−1)|
|Creatinine||134 μmol.l−1||(60–120 μmol.l−1)|
|Bilirubin||52 μmol.l−1||(2–17 μmol.l−1)|
|Alanine transferase||68 IU.l−1||(5–40 IU.l−1)|
|Lactate dehydrogenase||4183 IU.l−1||(300–650 IU.l−1)|
|C-reactive protein||21 mg.l−1||(1–6 mg.l−1)|
|(Other routine biochemical tests were all normal)|
|IgG antibodies directed against ADAMTS-13||Present|
|Computed tomography scan (brain)||Normal|
|Blood & urine cultures||Sterile|
Due to the level of extreme agitation and confusion, he underwent rapid sequence induction. His trachea was intubated and ventilation controlled artificially in the accident and emergency department to ensure both patient and carer safety. He was transferred to the critical care unit via CT scan. A diagnosis of TTP was made and he was started on plasma exchange overnight (within 4 h of admission). He continued on daily 3-l plasma exchanges. There were progressive neurological improvements and he was extubated with a Glasgow Coma Score of 15 on day 3. Unfortunately, despite initial improvements, his platelet count dropped significantly (Fig. 1) on day 6 and he developed digital ischaemia of his dominant hand. Intravenous prostacyclin (Flolan®) was started at 5 μg.kg−1.min−1 in addition to the ongoing daily plasma exchange. The platelet count continued to plummet and on day 7 rituximab (MabThera®) at a dose of 375 mg.m−2 was given. Thereafter a progressive improvement in both digital ischaemia and platelet counts were noted. Plasma exchange was continued for 21 days and the rituximab was given weekly for a total of 4 weeks. On discharge (day 29) his platelet count had stabilized (205 × 109 l−1). He has since been reviewed in clinic and remains well.
In the normal microcirculation a protein, von Willebrand factor (vWF), is required for platelet adhesion. Unusually large (ULvWF) groups of these protein molecules (multimers) can result in the formation of platelet thrombi within the vasculature. These molecules are physiologically cleaved by a plasma enzyme (metalloproteinase) known as ADAMTS-13 from the thrombospondin family of multifunctional proteins. ADAMTS-13 (a disintegrin-like and metalloproteinase with thrombospondin) degrades ULvWF into smaller multimers, preventing the formation of platelet thrombi. The characteristic features of TTP relate to the presence of vWF-rich platelet thrombi in arterioles and capillaries. ADAMTS-13 deficiency has been reported in cases of acute TTP.
Two main forms of TTP are distinguished. Hereditary TTP (Upshaw-Schulman syndrome) results in ADAMTS-13 deficiency due to genetic mutation. Acquired forms of ADAMTS-13 deficiency appear to be due to the presence of circulating auto-antibodies to ADAMTS-13 . A number of precipitating causes have been identified, including malignancy, immunological diseases, human immunodeficiency virus infection, pregnancy, anti-platelet therapy (clopidogrel and ticlopidine) and certain immunosuppressant agents.
Plasma therapy (plasma infusion and plasma exchange) remains the standard treatment for acquired TTP and leads to improved survival. Additional therapies are available for refractory or relapsing cases. In these situations, the aim is to clear ADAMTS-13 antibodies and restore significant ADAMTS-13 plasma activity.
Rituximab is a genetically engineered chimeric monoclonal antibody against the CD20 antigen expressed on the surface of B lymphocytes. Administration of the drug results in a rapid and sustained depletion of circulating and tissue-based B-cells. Reductions in both IgM and IgG serum levels are seen. B-cell recovery begins at approximately 6 months, with levels returning to normal by 12 months following completion of treatment.
In combination with methotrexate, rituximab is recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to or intolerance of other disease-modifying anti-rheumatic drugs (DMARDs), including treatment with at least one tumour necrosis factor α (TNF-α) inhibitor therapy. Rituximab within its licensed indication (that is, in combination with cyclophosphamide, vincristine and prednisolone) is also recommended as an option for the treatment of symptomatic stage III and IV follicular lymphoma in previously untreated patients. It has also been used in the treatment of refractory cases of non-Hodgkin’s lymphoma. The dose in refractory rheumatoid arthritis is two 1000 mg intravenous infusions separated by 2 weeks. The dose for lymphoma is 375 mg.m−2 given weekly for up to eight cycles. In refractory lymphoma 375 mg.m−2 is given weekly for 4 weeks. The drug is contraindicated in those with previous hypersensitivity, active infection and severe heart failure. Side effects include infusion reactions, tumour lysis syndrome (especially with large tumour burden), hepatitis B reactivation with fulminant hepatitis, cardiac arrhythmias and mucocutaneous reactions.
The drug has been used successfully in the treatment of TTP [6, 7]. In the presence of reduced ADAMTS-13 activity, patients with TTP refractory to plasma exchange may respond to rituximab as early as 7 days after admission . In the case described the diagnosis of TTP was based on clinical history and readily available laboratory tests allowing plasma exchange to be started overnight. ADAMTS-13 levels were not sent until the following morning post plasma therapy, which may explain why there was only a moderate reduction in levels. However the presence of autoantibodies directed against ADAMTS-13 were detected. Usually ADAMTS-13 activity levels are dramatically reduced (< 5%). Infusion of plasma and plasma exchange aims to increase ADAMTS-13 levels from external sources.
Vaccination is an important part of preventative medicine and undoubtedly reduces morbidity and mortality. Only in a few rare cases has vaccination been associated with autoimmune pathology. A form of Guillain-Barré syndrome was associated with the 1976–77 vaccination against swine influenza . Isolated case reports linking influenza vaccine with thrombocytopenia have been published . In this case any other precipitating cause was excluded. There was no prior platelet dysfunction, no additional medication apart from the recent vaccination, no evidence of sepsis or underlying malignancy and he was considered low risk for acquiring immunodeficiency. We could find only one similar case report of thrombotic thrombocytopenic purpura following influenza vaccination .
In conclusion vaccination is only rarely associated with autoimmune pathology. Plasma exchange remains the mainstay of treatment for TTP but additional therapies may be needed in refractory cases. Rituximab appears to be effective and well tolerated in the treatment of acute refractory thrombotic thrombocytopenic purpura.
Consent for publication has been granted by the patient.