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
  • HUS with diarrhea – E. coli or Shigella H or I testing
  • HUS with suspected S. pneumoniae – cultures, direct Coombs (positive ~90%)
  • HUS without cause – factors H, I
    • Consider autoimmune and HIV testing

Differential Diagnosis

• Acute renal failure due to other causes
• Adverse drug reaction
• Metastatic malignancy
• Disseminated intervascular coagulation (DIC)
• Heparin-associated antibody syndrome
• Malignant hypertension
• Pregnancy-related TMA
• Sepsis
• Stroke
• Evans syndrome
• Preeclampsia/eclampsia/HELLP
• Catastrophic antiphospholipid syndrome
• Immune thrombocytopenic purpura

Monitoring

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

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

Test Name and Number	Comments
Bilirubin, Direct & 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