Thrombotic thrombocytopaenic purpura is a rare blood disorder characterised by clot formation in small blood vessels, reduced platelet count, and neurological abnormalities with characteristic brain MRI findings of multiple, small, punctate hyperintensities on FLAIR and DWI sequences.
Description
Thrombotic thrombocytopenic purpura (TTP) is a form of thrombotic microangiopathy that is characterised by a pentad of fever, thrombocytopenia, microangiopathic haemolytic anemia, renal insufficiency, and neurological abnormalities. The condition arises from the deficiency or dysfunction of the enzyme ADAMTS13, leading to the accumulation of ultra-large von Willebrand factor multimers and widespread microvascular thrombosis.
Pathogenesis
In TTP, an inherited or acquired deficiency of ADAMTS13 impairs cleavage of von Willebrand factor multimers, leading to their accumulation. This in turn promotes platelet aggregation and thrombosis within small vessels, particularly in the brain and kidneys.
Subtypes
- Idiopathic or primary TTP: Thought to be due to autoantibodies against ADAMTS13.
- Secondary TTP: Associated with conditions such as pregnancy, HIV, malignancies, or certain medications.
Epidemiology, Risk Factors & Associations
- More common in adults than in children, with a peak incidence in the third decade.
- Affects women more often than men.
- African-American ethnicity is associated with an increased risk.
Clinical Features
Presents with a pentad of:
- Fever
- Thrombocytopenia (leading to purpura and mucocutaneous bleeding)
- Microangiopathic haemolytic anaemia
- Renal insufficiency (may present as proteinuria, haematuria, or renal failure)
- Neurological abnormalities (ranging from confusion and headache to seizures and stroke)
Complications
- TTP is a medical emergency, as it can rapidly lead to life-threatening organ damage or failure.
- Neurological complications can be severe and may include stroke or transient ischemic attack.
Pathological Features
Histopathology
- Macroscopic: No specific findings.
- Microscopic: Thrombi composed of platelets and fibrin can be found in small vessels.
Serology
- Characterised by severe ADAMTS13 deficiency (<10% of normal activity).
Biochemistry
- Evidence of haemolytic anaemia (e.g., elevated lactate dehydrogenase, decreased haptoglobin, presence of schistocytes on peripheral blood smear).
Radiological Features
General Features
- Characteristically demonstrates punctate hyperintensities on FLAIR and DWI brain MRI.
Brain MRI
- T1WI: Ischaemic lesions may be hypointense.
- T2WI: Ischaemic lesions may be hyperintense.
- FLAIR: Multiple, small, punctate hyperintensities.
- DWI/ADC: Restricted diffusion in acute ischaemic lesions.
Diagnosis
The diagnosis is based on clinical features and laboratory findings of microangiopathic haemolytic anaemia and thrombocytopenia. Severe ADAMTS13 deficiency confirms the diagnosis.
Differential Diagnosis
- Haemolytic Uremic Syndrome (HUS): Similar presentation with thrombocytopenia and microangiopathic haemolytic anemia. However, HUS is typically associated with preceding diarrheal illness (especially due to E. coli O157:H7 or Shigella dysenteriae) and more prominently features renal symptoms. Neurologic involvement is less common than in TTP. ADAMTS13 activity is typically normal or mildly decreased in HUS.
- Disseminated Intravascular Coagulation (DIC): This condition also presents with thrombocytopenia and microangiopathic haemolytic anemia. It is often associated with severe underlying conditions such as sepsis, malignancy, trauma, or obstetric complications. Unlike TTP, DIC is characterised by a broad range of coagulation abnormalities including prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), elevated D-dimer, and decreased fibrinogen.
- Systemic Lupus Erythematosus (SLE): Can occasionally mimic TTP with thrombocytopenia and microangiopathic haemolytic anemia, often in the context of a lupus flare. SLE often presents with additional symptoms such as rash, arthritis, serositis, renal disease, and positive antinuclear antibodies (ANA).
- Antiphospholipid Syndrome (APS): This autoimmune condition can lead to thrombocytopenia and vascular thrombosis, possibly mimicking TTP. APS is characterised by the presence of antiphospholipid antibodies, and vascular thrombosis in APS can occur in any location, not just microvasculature.
Management
Urgent plasma exchange is the mainstay of treatment, alongside corticosteroids. Rituximab can be used for refractory or recurrent disease. In emergencies, platelet transfusions may be needed, but they are generally avoided due to the risk of exacerbating thrombosis.