Thrombotic Microangiopathies - TMA

Thrombotic microangiopathy (TMA) syndromes can be acquired or hereditary. Primary TMAs include TMA with ADAMTS13 deficiency (commonly referred to as thrombotic thrombocytopenic purpura [TTP]), Shiga-toxin mediated TMA (also known as Shiga toxin TMA [ST-HUS]) and complement-mediated TMA (also known as atypical HUS [aHUS]). These disorders are associated with hemolysis (anemia), thrombocytopenia, and renal dysfunction in adults and children.

Epidemiology

• Incidence of acquired TTP
  • Adults – 2.9/million
  • Children – 0.1/million
• Age
  • TTP – usually adults, except for inherited forms
  • HUS – bimodal distribution: children (1-5 years) and older adults
  • aHUS – inherited disorder that affects children and adults; often presents in childhood
• Sex – M:F, equal

Risk Factors

• TTP
  • African American ethnicity
  • Autoimmune disorders
  • Malignancy (eg, lymphoma)
  • Certain drugs (eg, quinine)
  • Obesity
  • Pregnancy
• HUS
  • Gastroenteritis
  • Use of antimotility drugs or antibiotics during the course of bacterial diarrheas
•  aHUS
  • Mutations in genes coding for complement factors H, I, membrane co-factor protein, or other complement factors or regulatory factors cause aHUS (not associated with a diarrheal prodrome)

Pathophysiology

• Arteriolar platelet thrombi leads to thrombocytopenia, mechanical destruction of red blood cells (microangiopathic hemolytic anemia), and organ ischemia
• Severe deficiency of ADAMTS13 (von Willebrand factor cleaving protease) in adult-acquired and pediatric hereditary deficiency TMAs
  • Severe deficiency  – <5% of normal activity
• HUS is generally caused by bacterial infection with direct endothelial damage resulting in platelet thrombi
  • Enterohemorrhagic E. coli most common in U.S.
  • Shigella dysenteriae type I in developing countries
• aHUS is an inherited disorder of complement dysregulation caused by mutations in complement proteins or complement regulatory proteins

Clinical Presentation

• Primary TMA syndromes
  • Acquired TMA syndromes

    Acquired TMA Syndromes
    Syndrome	Etiology	Features	Age	Comorbidity Associations
    TTP (ADAMTS13 deficiency-mediated TMA)	Autoantibody inhibition of ADAMTS13 activity	Pentad of clinical findings (full pentad not always present) Microangiopathic hemolytic anemia Thrombocytopenia Fever Mental confusion, fluctuating neurological deficits, seizures, coma Abnormal urinalysis (hematuria) with occasional mild renal insufficiency Nonspecific symptoms – nausea, vomiting, diarrhea, abdominal pain, weakness	Usually adults; uncommon in children	Triggers – pregnancy, infection, inflammation, surgery, trauma Inducers of inhibitors – ticlopidine, HIV, autoimmune diseases, hematopoietic stem cell transplantation (HSCT)
    ST-HUS	Enteric infection with a Shiga toxin-secreting strain of E. coli or Shigella dysenteriae	Typically follows diarrheal illness Renal impairment (more severe than in TTP), oliguria, hematuria Hypertension Thrombocytopenia but bleeding manifestations rare Classical HUS (but not aHUS) typically follows diarrheal illness	More commonly in young children and elderly adults	Inducers – Shiga toxin, microbial neuraminidases
    Drug-mediated TMA (immune reaction)	Drug-dependent antibodies	Sudden onset of severe systemic symptoms Anuric acute kidney injury (AKI)	Any age	Inducers – quinine
    Drug-mediated TMA (toxic dose-related reaction)	Several potential mechanisms	Gradual onset of renal failure over weeks or months Hypertension	Any age	Inducers – VEGF inhibitors
    aHUS (complement-mediated TMA)	Antibody inhibition of complement factor H activity	AKI	Any age	Triggers: pregnancy, IV contrast agents, pancreatitis infection, inflammation, surgery, trauma Inducers – HSCT
    References: Tsai, 2013; George, 2014

    Hereditary TMA Syndromes

    Hereditary TMA Syndromes
    Syndrome	Etiology	Features	Age	Comorbidity Associations
    TTP (ADAMTS13 deficiency-mediated TMA) Also known as Upshaw-Schulman syndrome	Mutations in ADAMTS13 gene Autoantibody inhibition of ADAMTS13	Heterozygotes – asymptomatic Recurrent episodes of microangiopathic hemolytic anemia and thrombocytopenia May have acute ischemic organ injury AKI uncommon Neurological deficits	Usually children	n/a
    aHUS (complement-mediated TMA)	Mutations in genes CFH, CFI, CFB, C3, CD46, and others that cause uncontrolled activation of the alternative pathway of complement	Heterozygotes may have symptoms AKI common Hypertension	Usually children, but also adults	n/a
    Metabolism-mediated TMA	Homozygous or compound heterozygous mutations in MMACHC gene	Developmental abnormalities Neurological deficits Renal disease is variable	Typically children <1 year of age	n/a
    Coagulation-mediated TMA	Homozygous mutations in DGKE and possibly PLG and THBD genes	AKI	Typically children <1 year of age	n/a
    References: Tsai, 2013; George, 2014