Thrombotic Microangiopathies - TMA

Diagnosis

Indications for Testing

  • Presence of hemolytic anemia and thrombocytopenia with a clinical presentation suspicious for a thrombotic microangiopathy (TMA)

Laboratory Testing

  • Initial hematologic testing
    • Hemolytic testing
      • CBC – usually demonstrates thrombocytopenia and anemia
      • Peripheral smear – evidence of hemolysis with red blood cell fragments (schistocytes, burr cells, helmet cells) and reticulocytes
      • Serologic testing for intravascular hemolysis – increased indirect bilirubin, negative Coombs testing, increased lactate dehydrogenase (LD), decreased haptoglobin
    • Coagulation testing
      • Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen – all usually normal
      • D-dimer – may be normal or slightly elevated
  • Other testing
    • Blood urea nitrogen (BUN)/creatinine – usually elevated
      • May have acute kidney injury with marked elevation
    • Hemolytic uremic syndrome (HUS) presenting with diarrhea (Shiga-toxin mediated TMA [ST-HUS]) – E. coli/Shigella dysentery testing
  • Specific testing
    • ADAMTS13 activity
      • Specimen must be drawn before plasma exchange is started
      • May be low in disease states other than thrombotic thrombocytopenic purpura (TTP) (including other TMAs), but usually at least 25% of normal
        • <5-10% of normal suggests ADAMTS13 deficiency-mediated TMA
    • Anti-ADAMTS13 inhibitor/antibodies – absence in TTP suggests congenital disease; present in acquired TTP and may impart prognostic information
    • TMA with normal ADAMTS13 activity and no other obvious etiology – consider
      • Atypical HUS (aHUS) – rule out TTP and ST-HUS
        • Testing for complement abnormalities (complement factors H, I, and others) is not widely available and identifies causative abnormalities in only ~50% of cases
      • Autoimmune testing
      • HIV testing

Differential Diagnosis

Monitoring

  • Persistent ADAMST13 <10% of normal or presence of inhibitor or anti-ADAMST13 in clinical remission may signify risk of relapse

Clinical Background

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-mediated 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
  • 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

      Inducer 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)

      • Mutations in ADAMTS13 gene
      • Absence of ADAMTS13 autoantibody inhibitor
      • 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

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
ADAMTS13 Activity 0030056
Method: Fluorescence Resonance Energy Transfer

Useful to evaluate ADAMST13 deficiency as etiology for thrombotic microangiopathy (TMA)

Specimen must be drawn prior to beginning plasma infusion or exchange

Mild to moderate ADAMST13 deficiency may be seen in a variety of medical conditions

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Evaluate anemia and/or thrombocytopenia

Urea Nitrogen, Serum or Plasma 0020023
Method: Quantitative Spectrophotometry

Evaluate renal function

Creatinine, Serum or Plasma 0020025
Method: Quantitative Enzymatic

Evaluate renal function

Lactate Dehydrogenase, Serum or Plasma 0020006
Method: Quantitative Enzymatic

Evaluate anemia

Direct Coombs (Anti-Human Globulin) 0013008
Method: Hemagglutination

Evaluate for immune hemolytic anemia

Antibody Detection, RBC 0010004
Method: Hemagglutination

Evaluate for immune hemolytic anemia

Prothrombin Time 0030215
Method: Electromagnetic Mechanical Clot Detection

Evaluate for disseminated intravascular coagulation (DIC)

Usually normal or only slightly abnormal in TMA patients

Partial Thromboplastin Time 0030235
Method: Electromagnetic Mechanical Clot Detection

Evaluate for DIC

Fibrinogen Panel 0030137
Method: Electromagnetic Mechanical Clot Detection/Radial Immunodiffusion

Evaluate for DIC

D-Dimer 0030057
Method: Immunoturbidimetry

Evaluate for DIC

Haptoglobin 0050280
Method: Quantitative Immunoturbidimetry

Evaluate anemia

Urinalysis, Complete 0020350
Method: Reflectance Spectrophotometry/Microscopy

Evaluate renal function

Stool Culture and E. coli Shiga-like Toxin by EIA 0060134
Method: Culture/Identification

Rule out Shiga-toxin mediated TMA

Routine stool culture includes culture for Salmonella, Shigella, Campylobacter, and E. coli 0157 as well as EIA for Shiga-like toxin from E. coli