Thrombotic Microangiopathies - TMA

Epidemiology

• Incidence
  • 3-11/million people (Saha, 2017)
• Age
  • Thrombotic thrombocytopenic purpura (TTP) – first acute episode usually occurs during adulthood (~90% of all cases), except in inherited forms (Joly, 2016)
  • Hemolytic uremic syndrome (HUS) – bimodal distribution
    • Children (1-5 years)
    • Older adults
  • Complement-mediated HUS or atypical HUS (aHUS) – inherited disorder that affects children and adults; often presents in childhood
• Sex – M<F, 1:2 (Joly, 2016)

Risk Factors

• TTP
  • Predisposing factors (Joly, 2016)
    • Black ethnicity
    • Female gender
    • HLA-DRB1*11
    • Obesity
  • Precipitating factors (Joly, 2016)
    • Conditions increasing von Willebrand factor (VWF) levels (eg, inflammation, infections, pregnancy)
• HUS
  • Gastroenteritis
  • Use of antimotility drugs or antibiotics during the course of bacterial diarrheas
• aHUS
  • Variants in genes coding for complement factors H, I, membrane cofactor 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 TTP
  • Severe deficiency – <10% 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 (only rarely acquired) 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-mediated deficiency 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, HSCT
    STEC-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 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
    aHUS = atypical hemolytic uremic syndrome; AKI = anuric acute kidney injury; HSCT = hematopoietic stem cell transplantation; HUS = hemolytic uremic syndrome; IV = intravenous; STEC-HUS = Shiga toxin TMA; TMA = thrombotic microangiopathy; TTP = thrombotic thrombocytopenic purpura; VEGF = vascular endothelial growth factor 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	Variants in ADAMTS13 gene	Heterozygotes – asymptomatic Recurrent episodes of microangiopathic hemolytic anemia and thrombocytopenia May have acute ischemic organ injury AKI uncommon Neurological abnormalities	Usually children, but also adults	N/A
    aHUS (complement-mediated TMA)	Variants 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 variants in MMACHC gene	Developmental abnormalities Neurological deficits Renal disease is variable	Typically children <1 year	N/A
    Coagulation-mediated TMA	Homozygous variants in DGKE and possibly PLG and THBD genes	AKI	Typically children <1 year	N/A
    aHUS = atypical hemolytic uremic syndrome; AKI = anuric acute kidney injury; TMA = thrombotic microangiopathy; TTP = thrombotic thrombocytopenic purpura References: Tsai, 2013; George, 2014