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Thrombotic thrombocytopenic purpura (TTP) is a relatively rare disorder, which is reported as occurring at a rate of approximately six cases per million per year in the UK. Untreated, it can be fatal in up to 90 per cent of patients, with up to 50 per cent of those mortalities occurring within the first 24 hours. However, with the availability of plasmapheresis as an early treatment option, this figure has been reduced to somewhere in the region of 10-to-20 per cent.
TTP develops as a result of a deficiency of protease called A Disintegrin and metalloproteinase, with a thromboSpondin type 1 motif, member 13 (ADAMTS 13). In the absence of pathology, the role of ADAMTS 13 is to keep a large, multimeric glycoprotein called von Willebrand Factor (vWF) in check by cleaving it into smaller pieces.
vWF’s role is to attach to the endothelium of a damaged blood vessel and provide a meshwork to which platelets can aggregate. This in turn facilitates haemostasis. Unchecked — ie, without being cleaved by ADAMTS 13 — the large vWF results in the formation of larger platelet aggregates called microthrombi (see Figure 1). These large microthrombi consume platelets, lodge in the microvasculature of vital organs (most notably the brain, heart and kidneys) and result in a wide range of complications (see Table 1).
Table 1: Presenting features of TTP
The other effect the microthrombi have is to partially occlude blood vessels and cause fragmentation of erythrocytes as they are squeezed at high pressure through the remaining narrow lumens. This process is referred to as microangiopathic haemolytic anaemia (MAHA) and the fragments left behind are known as schistocytes.
The British Committee for Standards in Haematology (BCSH) has a comprehensive set of guidelines, which are generally followed by Irish haematologists. They recommend commencing treatment within four-to-eight hours of presentation to avoid mortality due to TTP. The challenge, as demonstrated by this case report, is that the clinical picture of a person who presents with TTP may evolve over a period of days before the treating physicians are able to arrive at a diagnosis.
Case report diagnosis
The haematology team was consulted with the results of the FBC and a blood film was requested for review. In a patient who presents with unexplained thrombocytopaenia and anaemia, one of the first things one should look to rule out is TTP. Bearing this in mind, the blood film was scrutinised, looking for schistocytes suggestive of MAHA (Image 2a). It showed thrombocytopaenia, moderate polychromasia and the occasional bite cell, but not enough red cell fragmentation to make a diagnosis, so other possibilities were considered. A coagulation screen was checked to rule out disseminated intravascular coagulation (DIC) and came back normal. The remainder of a haemolytic anaemia screen was also sent. This showed an elevated bilirubin (22.8umol/L), an elevated LDH (832 U/L), an elevated reticulocyte count (219.8 x109/L) and a low haptoglobin (<0.10 g/L), all consistent with intravascular haemolysis (Table 3).
Table 3: Haemolysis screen
The differential diagnosis at this point was very broad (Table 4). Renal impairment and a diarrhoeal prodrome in haemolytic uraemic syndrome (HUS) would be expected. Autoimmune haemolytic anaemia (AIHA) with immune thrombocytopenic purpura (ITP) — collectively known as Evan’s syndrome — was considered, however a negative direct Coomb’s test made this less likely. Bone marrow failure was also considered unlikely, given the elevated reticulocyte count, which suggested that the bone marrow was able to generate immature erythrocytes adequately. This was confirmed by a normal bone marrow biopsy.
Blood tests were sent to screen for an autoimmune cause, a viral cause, and other infections such as leptospirosis (Weil’s disease) and borrelia burgdorferi (Lyme disease), as all can potentially have haematological features and she had recently been hiking and camping in the Pyrenees in Spain. All results were ultimately negative. A CT scan of her thorax, abdomen and pelvis was also requested to see if this presentation could have been driven by some occult malignancy. It was also reported as unremarkable (Table 4).
Table 4: Differential diagnosis
Whilst awaiting this extensive battery of tests and their results, this patient was monitored with daily blood tests including an FBC, coagulation screen, renal function and a blood film. The results remained unchanged for the first five days of her admission. On the fifth day, she had a transient neurological event, which consisted of expressive dysphasia and some sensory disturbance. A CT brain scan was repeated to rule out an acute intracranial event such as a bleed, however this was again normal. A blood film repeated at the time of the event remained unchanged. The dysphasia resolved within three hours.
The following morning, a blood film was rechecked. It was found to be significantly different from the films of the preceding five days. For the first time, there was a marked number of schistocytes (Image 2b) consistent with MAHA.
She had also been febrile again overnight and her serum creatinine had risen to slightly above normal.
By day six of her admission, the patient had demonstrated all five features of the classic pentad of TTP (Table 5). It is however a disease with very variable features: They won’t all be present in every case. On that basis, the guidelines have changed in recent years to advise that a diagnosis of TTP must be suspected in any patient with thrombocytopenia and MAHA alone.
Table 5: Classic pentad vs new criteria
The diagnosis was confirmed by sending an ADAMTS 13 activity level and checking for anti-ADAMTS13 antibodies. The activity level was decreased at <1.0 per cent. A level of <5 per cent confirms the diagnosis. There were antibodies present, suggesting that this was an acquired, immune-mediated disease rather than the extremely rare congenital deficiency of ADAMTS13.
These blood tests need to be sent prior to commencing plasmapheresis in order to be accurate. The result is not generally available for several weeks, so one should under no circumstances wait for a confirmatory result before treating suspected TTP. If in doubt, commence treatment. It can always be stopped at a later date if the result returns as negative.
After collaboration between the haematology, nephrology and transfusion services, a central venous line was placed and plasmapheresis was commenced within approximately five hours of the diagnosis being made. Plasmapheresis is a process that involves removing the patient’s blood through a central venous line, separating the plasma from the cells, and then replacing the removed plasma with donor plasma, before returning it to the patient’s circulation.
In TTP, plasmapheresis is believed to work in two ways: By removing the antibodies against ADAMTS 13, and by replenishing the body’s supply of normal ADAMTS 13 with that of the donor plasma. If there is a delay to accessing plasmapheresis, high-volume plasma infusions can be given in the interim.
Evidence suggests that there is a modest improvement in outcomes with the administration of high-dose IV steroid in patients with TTP. Rituximab should be considered in patients who have neurological or cardiac features on presentation.
This patient had flitting neurological events, so she received a total of four rituximab infusions. It can also be considered in refractory or worsening disease. Rituximab is a monoclonal antibody that targets CD20-presenting B-cells. It is thought to work by preventing the future production of antibodies against ADAMTS 13. Ideally, steroids and rituximab should be given at least four hours before plasmapheresis, so that they have time to take effect before being removed from the plasma.
Any patient having active haemolysis should receive oral folic acid supplementation to replenish their stores of this erythrocyte building-block. Once the platelet count rises above 50 x109/L, patients should be commenced on aspirin 75mg daily and a prophylactic dose of low molecular weight heparin (LMWH), as the risk of thrombosis then outweighs the risk of bleeding. If haemoglobin is <7.0g/dL (or higher if there is cardiac involvement), red cell transfusion is advised. Platelet transfusion is best avoided unless there is life-threatening haemorrhage, as it can theoretically worsen the widespread thrombosis underpinning the disease.
In the case report patient, the FBC, LDH, renal function and blood film were monitored daily. A notable increment in the platelet count was seen by day three of treatment, and remission was achieved by day eight. Remission is defined as a normal platelet count of >150 x109/L. Plasmapheresis should be continued for at least two days after remission has been attained.
The patient received a total of nine days of plasmapheresis, three days of intravenous methylprednisolone, and four weekly rituximab infusions. She was discharged after 28 days in hospital and has remained well and relapse-free on monthly follow-up. Patients need to be counselled on the possibility of relapse and followed up regularly.
The ADAMTS 13 level should be rechecked in remission. If the level is <5 per cent, there is a 38.5 per cent risk of relapse. These patients should be considered for prophylactic rituximab to reduce this risk.
At the time of print, this patient remained relapse-free at four months post-remission.
This case report provides a number of learning points for both haematologists and general physicians.
It represents a good example of the classic pentad of TTP. It is useful to be aware of this pentad in order to recognise the condition. Bear in mind that only MAHA and thrombocytopenia are required for a diagnosis, so one should not wait for all five to be present.
Once a diagnosis is made, it is important to inform all relevant services early, so that treatment can be commenced promptly and mortality thus reduced. The ADAMTS13 level and antibodies should then be sent prior to commencing plasmapheresis.
This case stresses the importance of not discounting TTP as diagnosis on the basis of one non-diagnostic blood film. If you are considering it as a possibility and don’t have another explanation, repeat the blood film regularly. Presentations may evolve and diagnoses may declare themselves after an interval. Performing regular blood films in such cases may lead to an earlier diagnosis and may save someone’s life.
References on request
A 56-year-old woman with a medical history only significant for hypothyroidism and osteoarthritis presented to the emergency department with an episode of what she and her husband described as “confusion”. She also described a headache and one episode of vomiting. She had a low-grade pyrexia of 37.9oC on arrival.
Given her symptoms, a CT brain scan was arranged to rule out an intracranial event such as a stroke or a space-occupying lesion. This was reported as normal. Given her fever, a septic screen was performed, including cultures of blood and urine and a chest x-ray, all of which were also reported as normal. Her full blood count (FBC), however, was markedly abnormal, demonstrating thrombocytopaenia (platelets 20 x109/L) and a normocytic anaemia (Hb 8.8 g/dL, MCV 85 fL).
She denied any bleeding, bruising or a diarrhoeal prodrome. Her renal function was unremarkable. Her most recent blood test, five months earlier, had been normal (Table 2).
Table 2: Initial work-up