Thrombotic Microangiopathies (TMA):

The term TMA encompasses a plethora of heterogeneous conditions characterized by microangiopathic hemolytic anemia, thrombocytopenia and a variable degree of organ damage. Due to overlapping phenotypes and clinical presentation between the different conditions, the TMAs represent a challenge for clinicians. A number of the TMA disorders have known acquired, complement and/or functional drivers, which can be identified by Complement Functional Testing:

• Thrombotic Thrombocytopenic Purpura (TTP):
  • TTP is a rare disorder characterized by intravascular thrombotic lesions.  It is classically defined by the pentad of: 1) microangiopathic hemolytic anemia; 2) thrombocytopenia purpura; 3) neurologic abnormalities; 4) fever; and 5) renal disease.   The underlying cause is decreased or absent ADAMTS13 activity, leading to a hypercoagulable state.  TTP is most frequently caused by an inhibitor to ADAMTS13, anti-ADAMTS13 antibodies (acquired).  Rarely, TTP results from either homozygous or compound heterozygous ADAMTS13 gene mutations (genetic).
  • Thrombotic thrombocytopenic purpura. Joly BS et al. Blood. 2017 May 25;129(21):2836-2846.
• Complement-mediated atypical Hemolytic Uremic Syndrome (aHUS):
  • Complement-mediated aHUS is a form of TMA resulting from complement dysregulation at the endothelial cell surface in the microvasculature.  Disease is triggered by abnormalities of the alternate pathway (AP) of complement.  These abnormalities are most often inherited (genetic) but they can also be acquired in the form of autoantibodies most commonly against the complement factor H (FH) protein (FH autoantibodies, FHAA).
  • Genetic Analysis of 400 Patients Refines Understanding and Implicates a New Gene in Atypical Hemolytic Uremic Syndrome. Bu F. et al. J Am Soc Nephrol. 2018 Dec;29(12):2809-2819.
• C3 Glomerulopathy:
  • C3 Glomerulopathy (C3G) is a set of complement-mediated renal diseases characterized by predominant C3 deposition within the glomerular basement membrane as detected on immunofluorescence of the renal biopsy. C3G is further categorized into C3 glomerulonephritis (C3GN) or dense deposit disease (DDD) by electron microscopy. C3GN is defined by light, cloud-like subepithelial, intramembranous and subendothelial electron dense deposits, whereas DDD is defined by thicker, more dense deposits located within the lamina densa of the glomerular basement membrane. Both subtypes of C3G are driven by underlying dysregulation of the alternative pathway of the complement system. Drivers of complement dysregulation in C3G may include both genetic variation in complement genes and autoantibodies to complement proteins.  Disease is likely influenced by environmental triggers capable of primarily activating a complement immune response. Progression of the disease is heterogenous, with about 50% of individuals progressing to end stage renal disease within 10 years of diagnosis. Our mission at MORL is to identify and better define drivers of disease and with a goal toward facilitating the development of mechanistically driven, effective treatments for C3G.
  • High-Throughput Genetic Testing for Thrombotic Microangiopathies and C3 Glomerulopathies. Bu F et al. J Am Soc Nephrol. 2016 Apr: 27(4):1245-53.
  • C3 Glomerulopathy. Martín B, Smith RJH. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. updated 2018 Apr