TTP – Definitions

Definitions

• Thrombotic microangiopathies (TMA):
  • A group of heterogeneous disorders, characterized by:¹
    • Disseminated thrombus formation in arterioles and capillaries resulting in:
      • Thrombocytopenia
      • Microangiopathic hemolytic anemia (MAHA)
      • Potential end organ injury
  • Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies: “The term TMA is a pathologic term used to describe occlusive microvascular or macrovascular disease, often with intraluminal thrombus formation, but is also defined clinically by microangiopathic hemolytic anemia and thrombocytopenia (MAHAT).”²
  • “TMA represents a clinical manifestation of a histological condition marked by several features, including arteriolar and capillary thickening, detachment and swelling of endothelial cells, subendothelial widening, and the presence of platelet thrombi that obstruct the vascular lumen”.³
  • DynaMed: Thrombotic microangiopathy (TMA) is a group of syndromes with different etiologies, including ADAMTS13 deficient and nondeficient states, that share:
    • Clinical features of thrombocytopenia, microangiopathic hemolytic anemia, and organ injury
    • Pathologic features of occlusive microvascular or macrovascular disease, often with intraluminal thrombus formation
• Microangiopathic hemolytic anemia (MAHA):
  • Initially described to result from intravascular coagulation that leads to mechanical destruction of red blood cells (i.e. anemia and fragmentation of red blood cells) as they traverse through platelet and/or fibrin-rich thrombi.
  • Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies: “Peripheral blood film features consistent with MAHA include fragmented red blood cells (schistocytes), polychromasia [reflective of reticulocytosis], and anemia. Quantification of fragmentation/schistocytes is not reliably available and remains subjective. Laboratory evidence of [non-immune] hemolysis includes elevated lactate dehydrogenase (LDH), reticulocytosis, low/absent haptoglobin, and a negative direct antiglobulin test result.⁴
• Thrombotic thrombocytopenic purpura (TTP):
  • The definition for TTP has changed over time:
    • Initially, an acute episode of TTP was defined by both:
      • Clinical criteria (ischemic symptoms mainly targeting the brain)
      • Standard biology criteria:
        • Microangiopathic hemolytic anemia
        • Severe thrombocytopenia
      • Occurring in the absence of other apparent causes
    • Present day definition requires the presence of a severe deficiency of ADAMTS13 (activity <10%).
  • International consensus defines TTP as MAHA with moderate or severe thrombocytopenia, with associated organ dysfunction—this can include neurological, cardiac, gastrointestinal and renal involvement. The presence of specific organ dysfunction is not a prerequisite for diagnosis, which is confirmed by demonstrating a severe deficiency of ADAMTS13 (<10 IU/dL).⁵
  • Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies: “Definition of TTP: MAHA with moderate or severe thrombocytopenia, with associated organ dysfunction, including neurologic, cardiac, gastrointestinal and renal involvement, although oliguria or anuric renal failure requiring renal replacement therapy is not typically a feature. TTP is confirmed by a severe deficiency (<10%) of ADAMTS-13 activity.”⁶
  • DynaMed: “TTP is a thrombotic microangiopathy caused by a deficiency of von Willebrand factor cleaving protease, called ADAMTS13, which results in thrombocytopenia, microangiopathic hemolytic anemia, and widespread multiorgan thrombosis and injury.”
  • See TTP Classifications for definition of immune vs. congenital and primary vs. secondary TTP.
• Definitions of hematological response to treatment in TTP:⁷
  • Clinical response is defined as a sustained normalization of platelet count (for example, > 150 × 10⁹/L) and lactate dehydrogenase (LDH) level < 1.5 times the upper limit of normal after cessation of plasma exchange.
  • Clinical remission is defined as clinical response achieved after cessation of plasma exchange lasting > 30 days.
  • Exacerbation is defined as a fall in platelet count to below the lower limit of the reference range (for example, < 150 × 10⁹/L) requiring reinitiation of plasma exchange within 30 days of the last plasma exchange after initial clinical response had been achieved. This fall in platelet count is often accompanied by elevated LDH levels.
  • Relapse is defined as a fall in platelet count to below the lower limit of the reference range (for example, < 150 × 10⁹/L) requiring reinitiation of therapy > 30 days after completing plasma exchange for an acute TTP episode. This can occur with or without clinical symptoms and usually with a new increase in LDH levels.
  • Refractory TTP is defined as persistent thrombocytopenia (no sustained increase in platelet count or platelet count < 50 × 10⁹/L) and elevated LDH (> 1.5 times the upper limit of normal), despite 5 plasma exchanges and treatment with corticosteroid.

Want to explore this further?

Check out the related sections in our TTP module:

• TTP Definitions – Quiz
• TTP Classification