Thrombotic Thrombocytopenic Purpura

OVERVIEW

Thrombotic Thrombocytopenic Purpura (TTP) is a rare life-threatening condition that resembles HUS, the distinction is important because TTP can be treated with plasmapheresis

PATHOPHYSIOLOGY

• vWF synthesized in endothelial cells and assembled in larger multimers than those seen in plasma (ultra large vWF)
• rapidly degraded to normal sized multimers in plasma by the protease ADAMTS13
• in TTP there are autoantibodies against ADAMTS13
  -> accumulation of ULvWF
  -> platelet aggregation and clumping
  -> extensive microthrombi formation with haemolysis (MAHA) and end organ effects
• TTP may be triggered by an intercurrent event (e.g. surgery, pancreatitis, sepsis, pregnancy) resulting in endothelial activation

CLINICAL FEATURES

Classic pentad (FAT R/N)

• fever
• anaemia (microangiopathic haemolytic anaemia)
• thrombocytopenia
• renal problems (88% have renal problems, 15% haematuria) – more likely in HUS than TTP
• neurological problems (headaches, confusion, seizures, intracranial hemorrhage, focal deficits) – more likely in TTP than HUS

Risk factors

• infection (enterohemorrhagic E.coli 0157) (classically HUS)
• drugs (calcineurin antagonists, clopidogrel, cyclosporin, ticlopidine)
• pregnancy
• SLE
• graft versus host disease
• HIV-1
• connective tissue disorders
• malignancy

INVESTIGATIONS

FBC

• anaemia
• thrombocytopenia
• variable neutrophilia (should exclude toxic appearance)

Peripheral Blood Film

• markers of microangiopathic anaemia
  -> polychromasia, schistocytes and spherocytes
  -> increased reticulocytes

Haemolysis Screen

• reduced haptoglobins
• increased LDH (this is the most sensitive marker of severity and disease activity)
• unconjugated hyperbilirubinaemia
• increased urinary urobilinogen
• negative Coomb’s test (no antibodies bound to patient RBCs)

Urinalysis

• near normal
• exclude active sediment

Biochemistry

• increased urea and creatinine levels (greater in HUS)

Coagulation

• normal

CT Head

• excludes intracranial pathology as a cause for the seizures

Other microbiological cultures

• urine, blood, LP (often contra-indicated by thrombocytopenia)
• all should exclude active infection

ADAMTS13 protease

• low

Biopsy

• skin, muscle, gingival, lymph nodes, bone marrow -> typical microaneurysms and fibrin

MANAGEMENT

• plasmapheresis
  -> decreased mortality to < 10% (can perform plasma exchange up twice daily)
  -> initiate emergently
  -> FFP or cryoprecipitate replacement (not albumin)
  -> 1.5 plasma volumes daily until remission (plts >150)
• corticosteroids 1mg/kg/day
• seek and treat thrombotic complications
• don’t transfuse unless clinically indicated (e.g. life-threatening haemorrhage)
• daily platelets level until > 150 and LDH normal for 2-3 days
• rituximab IV (chimeric monoclonal anti-CD20 antibody – CD20 is mostly found on B cells)

References and Links

• Booth KK, Terrell DR, Vesely SK, George JN. Systemic infections mimicking thrombotic thrombocytopenic purpura. Am J Hematol. 2011 Sep;86(9):743-51. PMC3420338.
• Sadler JE. Thrombotic thrombocytopenic purpura: a moving target. Hematology Am Soc Hematol Educ Program. 2006:415-20. PMID: 17124092.
• Tsai HM. Pathophysiology of thrombotic thrombocytopenic purpura. Int J Hematol. 2010 Jan;91(1):1-19. PMC3159000.
• Eponymictionary. Moschcowitz disease (1925)
• Eponymictionary. Eli Moschcowitz (1879 – 1964)