Thrombotic Microangiopathies - TMA

Diagnosis

Indications for Testing

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

Laboratory Testing

  • CBC – usually demonstrates thrombocytopenia and anemia
  • Peripheral smear – evidence of hemolysis with red blood cell fragments (schistocytes, burr cells, helmet cells) and reticulocytes
  • BUN/creatinine – usually increased to a great degree in HUS versus TTP
  • Evidence of intravascular hemolysis – increased indirect bilirubin, negative Coombs testing, increased lactate dehydrogenase (LD), decreased haptoglobin
  • Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen usually normal 
    • D-dimer may be normal or slightly elevated
  • ADAMTS13 activity – not commonly used in diagnosis of TTP
    • Sample must be drawn before plasma exchange is started
    • May be low in disease states other than TMA but tends not to be <25% of normal
      • <5% suggests TTP
    • Drug-associated TTP – quinine, cyclosporine, tacrolimus, ticlopidine, clopidogrel
    • Anti-ADAMTS13 antibodies – absence suggests congenital disease
  • Other testing

Differential Diagnosis

Monitoring

  • ADAMTS13 levels have been successfully used in monitoring therapy
  • Persistent ADAMST13 <10% or presence of inhibitor or anti-ADAMST13 antibody signifies risk of relapse (threefold increase)

Clinical Background

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are thrombotic microangiopathies (TMA) associated with hemolysis (anemia), thrombocytopenia, and renal dysfunction in adults and children.

Epidemiology

  • Incidence – 4-10/1,000,000
  • Age
    • TTP – usually adults, except for inherited forms (Upshaw-Schulman syndrome)
    • HUS – bimodal distribution: children (1-5 years) and older adults
  • Sex – M:F, equal

Risk Factors

  • TTP
    • African American ethnicity
    • Autoimmune disorders
    • Certain drugs (eg, quinine)
    • Heredity – rare cases of familial TTP-HUS (Upshaw-Shulman syndrome)
    • Malignancy (eg, lymphoma)
    • Obesity
    • Pregnancy
  • HUS
    • Gastroenteritis (diarrhea-associated HUS)
      • Highest risk with Shiga-like toxin (verocytotoxin) producing bacteria
        • Most commonly Escherichia coli 0157:H7, although other E. coli serotypes and Shigella dysenteriae may be associated
    • Use of antimotility drugs or antibiotics during the course of infectious bacterial diarrheas
    • Streptococcus pneumoniae infection – neuraminidase production causes T-antigen exposure
    • Mutations in genes for complement factors H, I, or membrane co-factor protein cause atypical HUS (not associated with a diarrheal prodrome)

Pathophysiology

  • Arteriolar platelet thrombi leading to thrombocytopenia, mechanical destruction of red blood cells (microangiopathic hemolytic anemia), and organ ischemia
  • TTP is associated with severe deficiency of ADAMTS13 (von Willebrand factor cleaving protease)
    • Severe deficiency  – <5% of normal activity
    • TMA associated with autoimmune disease, malignancy, pregnancy, pancreatitis, medications or organ transplant (secondary forms) may not have severely deficient ADAMTS13 levels; these patients may not respond to plasma exchange
  • HUS is generally caused by bacterial infection and direct endothelial damage resulting in platelet thrombi
    • Enterohemorrhagic E. coli most common in U.S.
    • Shigella dysenteriae type I in developing countries
    • Rare causes – HIV, systemic lupus erythematosus, malignancy, radiation
    • Other causes – Streptococcus pneumoniae, complement dysregulation (factors H or I)
  • A variety of other TTP/HUS-like disorders exist and have different pathophysiology

Clinical Presentation

  • TTP
    • Pentad of clinical findings
      • Microangiopathic hemolytic anemia
      • Thrombocytopenia
      • Fever
      • Mental confusion, fluctuating neurologic deficits, seizures, coma
      • Abnormal urinalysis with occasional mild renal insufficiency, hematuria
    • Nonspecific symptoms – nausea, vomiting, diarrhea, abdominal pain, weakness
  • HUS
    • Microangiopathic hemolytic anemia
    • Thrombocytopenia – bleeding manifestations rare
    • Acute renal failure, oliguria, hematuria
    • Hypertension
    • Typically follows diarrheal illness

Treatment

  • TTP
    • Mainstay is plasma exchange, begun early in the disease course
      • Mortality approaches 90% in untreated patients
    • Immunosuppression, rituximab, or other treatments may also be used
  • HUS
    • Supportive

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
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Confirm anemia and thrombocytopenia

   
Urea Nitrogen, Serum or Plasma 0020023
Method: Quantitative Spectrophotometry

Assess for the presence of renal disease

   
Creatinine, Serum or Plasma 0020025
Method: Quantitative Enzymatic

Assess for the presence of renal disease

   
Lactate Dehydrogenase, Serum or Plasma 0020006
Method: Quantitative Enzymatic

Confirm hemolysis

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

Exclude immune hemolytic anemia

   
Antibody Detection, RBC 0010004
Method: Hemagglutination

Rule out immune hemolytic anemia

   
Prothrombin Time 0030215
Method: Electromagnetic Mechanical Clot Detection

Rule out DIC

Usually normal in TMA patients

   
Partial Thromboplastin Time 0030235
Method: Electromagnetic Mechanical Clot Detection

Rule out DIC

Usually normal in TMA patients

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

Rule out DIC

   
D-Dimer 0030057
Method: Immunoturbidimetry

Confirm or rule out DIC

   
ADAMTS13 Activity 0030056
Method: Fluorescence Resonance Energy Transfer
May be useful to distinguish TTP from HUS

Sample 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
Bilirubin, Direct and Total, Serum or Plasma 0020426
Method: Quantitative Spectrophotometry

Elevation of total and indirect bilirubin associated with hemolysis

Haptoglobin 0050280
Method: Quantitative Immunoturbidimetry

Decrease associated with hemolysis

Urinalysis, Complete 0020350
Method: Reflectance Spectrophotometry/Microscopy

Evaluate proteinuria and hematuria

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

Identification of Shiga-like toxin producing bacteria in patients with diarrhea indicates risk for subsequent HUS

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