Thrombotic Microangiopathies - TMA

Diagnostic Algorithm

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 in adults, except for inherited forms (Upshaw-Schulman syndrome)
  • HUS – bimodal distribution in children and older adults
• Sex – M:F, equal

Risk Factors

• TTP
  • Autoimmune disorders
  • African American ethnicity
  • Certain drugs (eg, quinine)
  • Malignancy (eg, lymphoma)
  • Obesity
  • Pregnancy
  • Heredity – rare cases of familial TTP-HUS (Upshaw-Shulman syndrome)
• 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 and I, membrane co-factor protein (MCP) 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 [vWF]-cleaving protease)
  • Severe deficiency = <5% of normal activity
• HUS is generally caused by bacterial infection and direct endothelial damage resulting in platelet thrombi
• 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
  • Acute renal failure, oliguria

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

Diagnosis

• Indications for testing – presence of hemolytic anemia and thrombocytopenia with a clinical presentation suspicious for a thrombotic microangiopathy
• Laboratory testing
  • Complete blood count – thrombocytopenia and anemia
  • Peripheral smear – evidence of hemolysis with red blood cell fragments (schistocytes, helmet cells) and reticulocytes
  • BUN/creatinine – usually increased; more so in HUS than TTP
  • Evidence of intravascular hemolysis – increased indirect bilirubin, negative Coombs testing, increased lactate dehydrogenase (LD), decreased haptoglobin
  • ADAMTS13 activity – 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 lower than 25% of normal
    • TMA associated with autoimmune disease, malignancy, pregnancy, medications or organ transplant (secondary forms) may not have severely deficient ADAMTS13 levels; these patients may not respond to plasma exchange
  • Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen usually normal
    • D-dimer may be normal or slightly elevated

Differential Diagnosis

• Acute renal failure due to other causes
• Adverse drug reaction
• Disseminated malignancy
• Disseminated intervascular coagulation (DIC)
• Heparin-associated antibody syndrome (HIT)
• Malignant hypertension
• Pregnancy-related TMA
• Sepsis
• Stroke
• Evans syndrome

Pharmacogenetics and Therapeutic Drug Monitoring

Screening

Monitoring

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Bilirubin, Direct & Total, Serum or Plasma 0020426 Method: Spectrophotometry	Elevation of total and indirect bilirubin associated with hemolysis
Haptoglobin 0050280 Method: Immunoturbidimetric	Decrease associated with hemolysis
Urinalysis, Complete 0020350 Method: Reflective Photometry/Microscopic by Yellow IRIS	Evaluate proteinuria and hematuria
Stool Culture, Routine (Includes E. coli Shiga-like Toxin by EIA 0060047) 0060134 Method: Standard reference procedures for Salmonella, Shigella, Shiga-like toxin producing E. coli, and Campylobacter culture and identification.	Identification of Shiga-like toxin producing bacteria in patients with diarrhea indicates risk for subsequent HUS
Prothrombin Time 0030215 Method: Electromagnetic Mechanical Clot Detection	Usually normal in TMA patients
Partial Thromboplastin Time 0030235 Method: Electromagnetic Mechanical Clot Detection	Usually normal in TMA patients

General References

References from the ARUP Institute for Clinical and Experimental Pathology®