This is a rare form of thrombotic microangiopathy. It is characterised by:

• Microangiopathic haemolysis
• Thrombocytopaenia
• Neurological abnormalities
• Fever
• Renal dysfunction

It is a life-threatening multisystem disorder that was first described by Moschcowitz in 1924.

Pathogenesis

It used to be considered part of the spectrum of haemolytic uraemic syndrome, but they have been subsequently found to be separate entities.

In most cases of familial thrombotic thrombocytopaenic purpura (TTP) and acquired idiopathic TTP, the endothelial cells secrete and release the ultralarge von Willebrand factor (ULVWF) multimers.

The ULVWF multimers trap platelets and bind to the subendothelium. ^1,2 There is a deficiency of ULVWF-cleaving protease activity in TTP patients and this has been suggested to be due to the presence of antibodies or a severe deficiency of ULVWF-cleaving protease.

Epidemiology

The incidence is rising as there is greater recognition of the condition. It is currently around 3.7 cases per million patients.

• The age-sex standardised incidence of thrombotic thrombocytopaenia purpura and haemolytic uraemic syndrome has been recently reported as 2.2 per million per year in the United Kingdom.³
• It is most common in adults, although it has been reported in neonates and nonogenarians. The peak occurs in the fourth decade of life.
• It is more common in females that males; the ratio is 3:2.

Aetiology

• Pregnancy and the postpartum state account for 10-25% of cases of TTP.⁴The course of the syndrome is not altered by termination of pregnancy.
• It occurs in greater frequency in patients with HIV infection; it may be the initial presenting syndrome.
• It is often associated with cancer.
• Cancer chemotherapeutic agents associated with TTP include mitomycin C, tamoxifen, bleomycin, cytosine arabinoside, and daunomycin.
• Chemotherapeutic and other drugs suspected of causing TTP include:
  • Immunosuppressive agents, e.g. cyclosporine A
  • Crack cocaine
  • Oral contraceptives
  • Penicillin and rifampin
• Toxins associated with TTP include the following:
  • Escherichia coli; E. coli O157:H7 is a toxin-producing bacterium
  • Spider and bee venoms

Presentation

There may be a prodrome resembling a flu-like illness, including fever, fatigue and generalised malaise and arthralgias. A patient can present with some or all of the characteristics of the classic pentad, which includes the following:

• Thrombocytopaenia; petechial haemorrhages in the lower extremities and a lack of bleeding.
• Other haematological changes; anaemia - haemoglobin levels less than 10 g/dL.
• Fever.
• Renal changes (88%) with gross haematuria, microscopic haematuria, raised urea and creatinine.⁴
• Neurological deficits:
  • These vary from small changes in affect, to aphasia, blindness and convulsions. There may also be fluctuating levels of consciousness, focal neurological signs, confusion and tremor

• Cardiac changes:
  • Arrhythmias
  • Heart failure
• Abdominal pain may be seen (associated with gastro-intestinal ischaemia).

Examination

This may be normal. However you may find:

• Fever
• Purpura - non-palpable small purpuric spots or petechiae occur with thrombocytopaenia, i.e. platelet count < 50 x 10⁹/L
  
  
• Jaundice - secondary to haemolysis
• Severe hypertension
• Neurological problems as above
• Splenomegaly

Investigations

• Blood smear shows fragmented erythrocytes, i.e. schistocytes. This is consistent with haemolysis. Schistocytes are a hallmark of the disease, but there are no guidelines as to the number of schistocytes required to differentiate TTP from other thrombotic microangiopathies.
• Renal function tests; creatinine level is mildly elevated in about half of patients.
• Coagulation studies are non-diagnostic.
• LDH level is extremely elevated. This is released from ischaemic or necrotic tissue cells.
• Indirect bilirubin level is elevated.
• Reticulocyte count is elevated.
• Urinalysis shows proteinuria and microscopic haematuria.

Management

Intravenous plasma exchange

Intravenous (IV) plasma exchange is also called plasmapheresis. It is the present standard of treatment for TTP. During the plasma exchange, the inhibitory antibodies are removed and the plasma is replenished with the deficient protease. Unfortunately the optimal exchange media is not yet known, nor the volume and duration of exchange therapy, nor appropriate salvage therapy. Without the benefit of randomised controlled trials, its treatment is not evidence-based. ⁵

• Infusion of fresh frozen plasma (FFP) 30 mL/kg used until the patient can be transferred to a facility where plasma exchange is available.
• Glucocorticoid steroid and antiplatelet agents are used. Steroids often are administered prior to plasma exchange. Steroids have no proven added benefit over plasmapheresis alone, but some patients respond to high-dose prednisone (200 mg/d) alone, without plasma therapy. Haemorrhage is a concern with anti-platelet therapy and its benefit has not been proven. ⁶
  Recently the use of rituximab, a monoclonal anti-CD20 antibody, has also become mainline treatment.⁷ This has been associated with fewer relapses.

Surgery

Splenectomy may be used to treat patients who do not respond to plasma exchange, or who relapse chronically. Some patients benefit from splenectomy.

Other measures

Supportive care for end-organ damage may be required, e.g. haemodialysis for renal failure.

Prognosis

Plasma exchange was introduced in the 1960s improving the survival rate from approximately 3% to 80-90%.⁴ Early recognition of the condition with plasma infusion and exchange has improved the outcome.

33% of patients who survive the initial episode, experience a relapse within the next 10 years.