Thrombotic Microangiopathies - TMA

Thrombotic microangiopathy (TMA) syndromes can be acquired or hereditary. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are two prototypes of TMAs, although TMAs may occur secondarily to multiple other systemic disorders (eg, malignant hypertension, medications). These disorders are associated with hemolysis (anemia), thrombocytopenia, and renal dysfunction in adults and children. TTP should be distinguished from other TMA syndromes, as patients with ADAMTS13 deficiency are likely to respond to therapeutic plasma exchange (TPE) whereas those without ADAMTS13 severe deficiency require treatments other than TPE (Joly, 2016).

Diagnosis

Indications for Testing

Definitions

  • Consensus on standard terminology and definitions (Scully, 2016)
    • Thrombotic thrombocytopenic purpura (TTP)
      • MAHA
      • Moderate or severe thrombocytopenia
      • Associated organ dysfunction
      • Severe deficiency (<10%) of ADAMTS13 activity
      • Subtypes of TTP
        • Congenital TTP (cTTP, or Upshaw-Schulman syndrome)
          • Persistent severe deficiency (<10%) of ADAMTS13 activity with no evidence of anti-ADAMTS13 inhibitory autoantibodies, confirmed by molecular analysis of ADAMTS-13 gene mutations
        • Immune-mediated TTP (iTTP) – acquired TTP
          • Primary iTTP – no obvious underlying precipitating cause/disease
            • Due to immune inhibitor of ADAMTS13
            • Accounts for the majority of cases of TTP
          • Secondary iTTP – underlying disorder or trigger can be identified (eg, infectious disease, drugs, pregnancy)
    • Hemolytic uremic syndrome (HUS)
      • Microangiopathic hemolytic anemia and thrombocytopenia (MAHAT)
      • Renal injury
      • Subtypes of HUS
        • Infection-associated HUS/classical (IA-HUS or STEC-HUS)
          • Infectious etiology typically associated with E. coli, which expresses Shiga toxin
        • Complement mediated/atypical (CM-HUS or aHUS)
          • Results from defective regulation of the alternative complement pathway
          • May be triggered by infection, vaccinations, or pregnancy

Laboratory Testing

  • Specific testing
    • ADAMTS13 investigation – sensitive and specific marker for TTP
      • Activity testing
        • Severe deficiency (<10%) – essentially diagnostic of TTP
        • Specimen must be drawn before plasma exchange is started; samples taken following plasma therapy may give a falsely raised ADAMTS13 activity (Scully, 2016)
        • May be low in disease states other than TTP (including other thrombotic microangiopathies [TMAs]), but usually at least 25% of normal
      • Antibody testing
        • ADAMTS13 autoantibodies can neutralize ADAMTS13 function (found in ~2/3 of idiopathic cases), increase clearance (found in ~1/3 of idiopathic cases), or both
        • Absence of antibodies in the presence of severely deficient ADAMTS13 activity suggests congenital disease
        • Inhibitor testing
          • Present in majority of acquired TTP and may impart prognostic information
        • Antibody testing
          • Not recommended as initial test for identification of autoantibodies to ADAMTS13 – antibody test is less specific for acquired TTP than inhibitor test
          • Consider when acquired TTP is suspected but antibodies are not identified by inhibitor testing
  • Nonspecific testing
    • Intravascular hemolysis testing
      • Bilirubin (increased), Coombs testing (negative), haptoglobin (decreased/absent), lactate dehydrogenase (LDH) (elevated)
    • Organ dysfunction testing
      • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT), creatinine
    • Coagulation testing
      • Prothrombin time (PT)/partial thromboplastin time (PTT)/d-dimer – usually normal
    • Hematology testing
      • CBC – demonstrates thrombocytopenia (typically <30 X 109/L) (Joly, 2016)
      • Blood smear – red blood cell fragmentation (schistocytes), high reticulocyte count (>120 X 109/L)
    • Other testing as needed
      • Antinuclear antibodies (ANA)
      • Stool culture
      • Shiga toxin stool polymerase chain reaction (PCR) – for patients presenting with diarrhea
      • Complement testing if aHUS suspected
  • Molecular analysis
    • ADAMTS13 testing
      • May be useful in suspected hereditary TTP (Upshaw-Schulman syndrome)
      • Suspected in patients with family history or when ADAMTS13 activity <10% and an inhibitor is not detected (Joly, 2016)

Differential Diagnosis

  • Differential diagnosis of TTP from other TMAs (Saha, 2017)
    • Medication induced
    • Chemotherapy induced
    • Transplantation associated
    • Malignancy related
    • Infectious (eg, HIV)
    • Disseminated intravascular coagulation (DIC)
    • Malignant hypertension
    • Pregnancy associated (eg, preeclampsia/eclampsia/Hemolysis, Elevated Liver enzyme levels, Low Platelet count (HELLP)

Monitoring

Persistent ADAMTS13 <10% of normal or presence of inhibitor of anti-ADAMTS13 in clinical remission may signify risk of relapse.

Background

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
    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
    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

ARUP Lab Tests

Reflexive panel to assist in diagnosis of thrombotic thrombocytopenic purpura (TTP) and in distinguishing between inherited and acquired forms of TTP

Reflex pattern: if ADAMTS13 activity is ≤30%, then ADAMTS13 inhibitor will be added; if ADAMTS13 inhibitor is <0.7 BU, then ADAMTS13 antibody will be added

Assist in diagnosing acquired (idiopathic) or inherited TTP

Specimen must be drawn prior to beginning plasma infusion or exchange

Mild to moderate ADAMTS13 deficiency may be seen in a variety of medical conditions

Assist in distinguishing between inherited and acquired forms of TTP

Recommended initial test for the identification of autoantibodies to ADAMTS13, since the ADAMTS13 inhibitor test is more specific for acquired TTP than the ADAMTS13 antibody test

If suspicion for TTP remains after a negative result, ADAMTS13 antibody is recommended

Assist in distinguishing between inherited and acquired forms of TTP

Not recommended as initial test for identification of autoantibodies to ADAMTS13, since the ADAMTS13 antibody test is less specific for acquired TTP than ADAMTS13 inhibitor

Order when acquired TTP is suspected but antibodies are not identified by the ADAMTS13 inhibitor test

Related Tests

Evaluate renal function

Assay interference (negative) may be observed when high concentrations of N-acetylcysteine (NAC) are present

Negative interference has also been reported with NAPQI (an acetaminophen metabolite), but only when concentrations are at or above those expected during acetaminophen overdose

Evaluate renal function

Initial test for suspected bleeding disorder

Evaluate anemia and/or thrombocytopenia

Identify antibodies as cause of hemolysis

Reflex pattern: for positive results for females 15-45 years of age, antibody identification, RBC (prenatal only) is added; for all other positive results, antibody ID package is added

Assist in diagnosing dysfibrinogenemia

Aid in diagnosing and following disseminated intravascular coagulation (DIC)

Evaluate for functional ability of the classical complement pathway

Evaluate for functional activity of alternative complement pathway

May assist in ruling out a complement deficiency

Evaluate for complement 3

May assist in ruling out a complement deficiency

Evaluate for complement 4

Screen for various metabolic and kidney disorders

Preferred test for suspected bacterial diarrhea evaluation

Testing includes cultures for Salmonella, Shigella, Campylobacter, E. coli O157, and EIA for Shiga-like toxin from E. coli

Can be used to rule out Aeromonas and Plesiomonas; specify the pathogen to rule out

   

Medical Experts

Contributor
Contributor

Smock

Kristi J. Smock, MD
Professor of Clinical Pathology, University of Utah
Medical Director, Hemostasis/Thrombosis, ARUP Laboratories

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®