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 genetic drivers, which can be identified by the Genetic Renal Panel: 

  • 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).
  •   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
  • DGKE TMA/C3G:
    • Recessive mutations in the diacylglycerol kinase epsilon (DGKE) gene, a gene distinct from the complement pathway, have been identified in patients with both TMA (1) and membranoproliferative GN (2). Common features observed in this subset of patients are early onset of disease (often < 2 yrs) and multiple disease relapses. Patients with homozygous or compound heterozygous variants in DGKE are typically considered eculizumab non-responsive.
      • Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Lemaire M. et al. Nat Genet. 2013 May;45(5):531-6.
      • DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN. Ozaltin F. et al. J Am Soc Nephrol. 2013 Feb;24(3):377-84.
  • Cobalamin Deficiency:
    • Defects of intracellular cobalamin metabolism represent a group of rare diseases that can lead to metabolism-mediated TMA. These inborn errors in intracellular vitamin B12 metabolism are usually diagnosed during the first year of life but can present with later onset and should be considered in the differential diagnosis of adults presenting with a TMA phenotype.
      • Vitamin B12 deficiency and metabolism-mediated thrombotic microangiopathy (MM-TMA). Sabry W. et al. Transfus Apher Sci. 2019 Dec 31:102717.
  • Glucose-6-phosphate dehydrogenase (G6PD) Deficiency:
    • G6PD deficiency is an X-linked hereditary genetic disorder commonly associated with acute hemolytic anemia provoked by infection or ingestion of specific foods or drugs.  G6PD related hemolysis is not classically associated with significant acute kidney injury (AKI) or thrombocytopenia. However, we and others have observed that some patients with a clinical diagnosis of TMA carry a pathogenic variant in the G6PD gene. The role of G6PD deficiency in contributing to the underlying pathology of a TMA-like presentation including thrombocytopenia and renal insufficiency is unknown.  Despite this gap in our understanding, considering G6PD deficiency in the differential may have diagnostic and treatment implications. For this reason, testing is recommended in the workup of a clinical TMA.
      • Glucose-6-Phosphate Dehydrogenase Deficiency Mimicking Atypical Hemolytic Uremic Syndrome. Walsh PR. et al. Am J Kidney Dis. 2018 Feb;71(2):287-290
  • 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 heterogeneous, 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.
  • Denys-Drash Syndrome
    • Denys-Drash syndrome (DDS), a rare disorder characterized by early-onset nephrotic syndrome and renal failure, pseudo-hermaphroditism, and a high risk of Wilms' tumor. Several cases of DDS presenting with atypical hemolytic uremic syndrome (aHUS) have been reported.
    • Hemolytic uremic syndrome (HUS) can occur as a primary process due to mutations in complement genes or secondary to another underlying disease. HUS sometimes occurs in the setting of glomerular diseases, and it has been described in association with Denys-Drash syndrome (DDS), which is characterized by the triad of abnormal genitourinary development; a pathognomonic glomerulopathy, diffuse mesangial sclerosis; and the development of Wilms tumor.

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The Clinical Diagnostics Service of the Molecular Otolaryngology and Renal Research Laboratories is a Joint Commission-approved CLIA-accredited diagnostic laboratory.