After a rather stormy few days the patient starts to improve. Thankfully an HDU/ICU stay is not needed and he manages to stay on the renal ward. S/D plasma exchange is continued with standard FFP and a further pulse of IV methylprednisolone is given along with rituximab 375mg/m2. Folic acid is also continued. A two unit blood transfusion was required when the Hb dropped to 73g/L and he was symptomatic When the patient continued to improve a CT scan of chest abdomen and pelvis is performed which is normal. Aspirin 75mg is started along with prophylactic LMWH as platelets reach 50. The plasma exchange is stopped after the platelet count has reached 150 for two consecutive days and the patient remains stable. After a further week of monitoring the patient is discharged from hospital with close follow up in the haematology clinic. Aspirin and folic acid are continued post discharge and his platelet count was 232.
TTP – introduction
TTP is a serious life threatening medical emergency. It is rare with approximately six cases per million per year in the UK. It is a type of microangiopathic haemolytic anaemia, of which other clinical syndromes can be similar:
- Haemolytic uraemic syndrome
- Malignant hypertension
- HELLP (haemolysis elevated liver enzymes low platelets)
- Disseminated intravascular coagulation
- Autoimmune diseases e.g. anti-phospholipid syndrome, SLE
Prompt therapy is paramount as most deaths occur within 24 hours of admission and it is 90% fatal if untreated.
TTP – pathogenesis
TTP is due to a lack of the ADAMTS13 enzyme which can be congenital (i.e. genetic) or acquired (autoantibody-related). The ADAMTS13 enzyme cleaves large multimers of von Willebrand Factor, of which the normal function is to aid in clotting by helping platelet aggregation. When large vWF multimers are in excess the causes microthrombosis in small vessels and lead to the clinical syndrome of TTP. End organ damage can lead to renal impairment, cardiac involvement and neurological sequelae. Intra vascular haemolysis occurs due to the haemoglobin being forced through blocked vessles i.e. shear forces. Thrombocytopenia occurs due to platelet consumption in platelet-rich thrombi.
TTP – clinical syndrome
The classic clinical presentation is often insidious in inset and consists of the pentad:
- Fluctuating neurological impairment – may include personality change and drowsiness to seizures and coma
- Renal failure*
In real life the classic presentation is often not present and doctors should have a low index of suspicion. Abdominal pain can occur and cardiac involvement is a sinister sign. Signs of bleeding such as epistaxis and petechial rashes occur. Patients may be jaundice due to hyperbilirubinaemia and may feel non-specifically unwell. *Patients with severe renal failure are more likely to have HUS.
TTP – Investigations
The below are to help in the diagnosis of other MAHA and also to point towards a potential cause.
- Biochemistry: U&E/LFT/Ca/indirect bili/LDH/troponin/amylase
- Haematology: FBC, film, reticulocyte count/coag/DAT
- Viral: HIV/Hep B/C
- Immunology: Autoimmune screen/haptoglobin
- ADAMTS13 assay
- CT head
- CT chest abdo pelvis, pregnancy test and stool sample if indicated
TTP – management
This is a medical emergency and management must begin immediately. Plasma exchange should be started ASAP in order to replace normal levels of ADAMTS13. If there is a delay in plasma exchange then FFP can be transfused but be aware for fluid overload. Depending on the service plasma exchanged may be done by the nephrologists, intensivists or haematologists. Using solvent/detergent-treated plasma may reduce the risk of transfusion-associated infection and is advised. 1.5 x plasma volume exchange per day is needed. The formula can be found on many medical apps or the internet. Plasma volume (L) = 0.065 x weight (kg) x (1-HCT (%)). This should be continued until the platelet count is >150 for two consecutive days and then stopped. This can be reduced to 1 x plasma volumes after three days if clinical improvement. The amount of exchange or frequency can be increased if no clinical improvement e.g. 2-3 x plasma volume and/or BD plasma exchange. Cryosupernatant (cryo-poor plasma) contains less vWF and therefore theoretically may produce better results however this is not supported by the evidence.
Once the platelet count is greater than 50 aspirin 75mg and prophylactic LMWH can be started due to risk of thrombosis. Other general measures include transfusion of red cells if needed and prescribing folic acid 5mg od. Methylprednisolone at 1g IV for three days is routine. Platelet transfusions should not be given unless life threatening bleeding as this can worsen the condition. If central lines need to be placed then this should be done using ultrasound in an experienced pair of hands.
Current UK guidelines state rituximab 375mg/m2 weekly for four weeks should be used as second line in non-responders or if neurological or cardiological sequelae. Other options are vincristine or ciclosporin but the evidence behind their use is lacking. Splenectomy is not advised in the acute setting but may rarely be considered if chronic.
BCSH guideline on TTP: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2012.09167.x/pdf
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