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2258 Part XII: Hemostasis and Thrombosis Chapter 132: Thrombotic Microangiopathies 2259

TTP usually occurs in the third trimester or postpartum, whereas fetal STEC causes HUS (STEC-HUS) that is usually is associated with a pro-
loss is most common in the second trimester. 109 drome of diarrhea. Other names in the literature for STEC-HUS include
diarrhea-associated HUS (D+HUS) and “typical” HUS.
LABORATORY FEATURES In 1955, the term HUS was proposed for thrombotic microan-
Severe congenital ADAMTS13 deficiency (<5 percent) is characteristic giopathy occurring in children and associated with acute anuric renal
115
of congenital TTP. Alloantibodies to ADAMTS13 as a consequence of failure, which is uncommon in TTP. HUS was often preceded by a
treatment with plasma are extremely rare in congenital TTP; only one diarrheal illness and, unlike TTP in adults, the prognosis was relatively
such patient has been reported. Other laboratory findings in congen- favorable. Most patients survived and recovered normal renal function
110
116
ital TTP are similar to those in acquired TTP. The histologic features of with only supportive care. Although cases were known to cluster in
congenital TTP are similar to those of acquired TTP. 111 endemic areas, the cause of HUS was unknown until 1983, when E. coli
O157:H7 was shown to express a Shiga-like toxin and cause epidemic
hemorrhagic colitis that could evolve into HUS. 117–119
DIFFERENTIAL DIAGNOSIS
For patients presenting during early childhood, other causes of throm- ETIOLOGY AND PATHOGENESIS
botic microangiopathy to consider include STEC-HUS, atypical HUS
and secondary thrombotic microangiopathy associated with disorders STEC may make two types of Shiga toxin (Stx) that are similar in struc-
that are characteristic of childhood. For adolescents and adults, the dif- ture and function to ricin. Stx1 is identical to Shigella dysenteriae sero-
ferential diagnosis is the same as for acquired TTP (see Table 132–1). type 1 toxin. Stx2 is approximately 50 percent identical in sequence to
Testing of stool and urine for STEC should be considered for all Stx1 and occurs in several closely related forms. Both toxins consist
patients with thrombotic microangiopathy because a significant frac- of pentameric B subunits that bind globotriaosylceramide (Gb3) on
tion of patients with STEC infection never have bloody diarrhea. cell surfaces and a single A subunit that is responsible for cytotoxicity.
Pathogenic E. coli almost always express a variant of Stx2 and approxi-
THERAPY mately two-thirds express Stx1. 120
When STEC colonize the gut they damage the epithelium and
Congenital TTP can be treated with periodic infusions of fresh-frozen secrete Stx that is delivered to target organs through the blood, probably
plasma or an equivalent virucidally treated product, if available. The by neutrophils. Stx bound to Gb3 on cell surfaces is endocytosed and
half-life of ADAMTS13 is 2 to 3 days and the level of ADAMTS13 transported in a retrograde fashion through the secretory pathway to
112
required to avoid symptoms is approximately 5 percent of normal; the endoplasmic reticulum, where the A subunit is translocated into the
5 to 20 mL/kg of plasma every 2 to 3 weeks usually is sufficient to main- cytoplasm. The A subunit is an N-glycosidase that removes a specific
tain ADAMTS13 at a greater than 5 percent level and prevent symp- base from the large ribosomal subunit, which inhibits protein synthesis
toms. 105,107 Patients with severe allergic reactions to plasma have been and activates a response pathway that leads to apoptosis. The observed
treated successfully with plasma-derived factor VIII/VWF concentrates predilection for renal injury is a result of the relatively high expression
that contain significant amounts of ADAMTS13. 55 of Gb3 on renal tubular epithelial, mesangial, and glomerular endothe-
lial cells.
Pregnancy Management
Fetal loss and premature birth can be prevented by plasma infusions
10 mL/kg every 2 weeks beginning at 8 weeks of gestation, increasing EPIDEMIOLOGY
to weekly in the second trimester. Any sign of thrombotic microangio- STEC-HUS can occur at any age but affects mainly children younger
pathy is an indication to increase the volume or frequency of plasma than age 5 years and is rare before age 6 months. The disease occurs spo-
infusion. Plasma exchange may be necessary to avoid fluid overload. 55,109 radically and in epidemics, associated with ingestion of foods or other
materials contaminated with Stx-producing bacteria. E. coli O157:H7
COURSE AND PROGNOSIS accounts for at least 80 percent of cases in many series, but STEC-HUS
can be caused by other toxin-bearing E. coli serotypes
or by S. dys-
121,122
The severity of congenital TTP varies considerably and correlates enteriae type 1. Most cases occur in summer and autumn in rural envi-
to some extent with the underlying genotype and residual plasma ronments. The incidence is approximately 10 to 30 per million children
ADAMTS13 activity. Patients with ADAMTS13 activity of less than 2.5 per year, but depends on the risk of exposure, which varies considerably
percent of normal tend to have their first TTP episode in childhood, with the time of year, location, and other factors. STEC-HUS is a com-
have more than one episode of TTP per year, and require regular plasma mon cause of chronic renal failure in children. 120
prophylaxis. Conversely, patients with ADAMTS13 activity of 2.5 to
6.0 percent tend to present in adulthood and have infrequent episodes CLINICAL FEATURES
of disease. 113,114 Some of these patients have prolonged symptom-free
intervals and can be treated on demand. However, inadequately treated Patients develop abdominal pain, tenderness and diarrhea between 2
patients are at risk for developing chronic renal failure and stroke. 55 and 12 days after ingesting STEC, with a mean incubation period of 3
to 7 days and a median of 3 days. The diarrhea usually becomes bloody
within 1 to 3 days, at which time patients are typically afebrile. Nausea
SHIGA TOXIN ESCHERICHIA and vomiting are common. The abdominal pain is greater than is typical
COLI–ASSOCIATED HEMOLYTIC for other causes of gastroenteritis, and defecation is often painful. Most
UREMIC SYNDROME patients recover spontaneously within a few days. Of children younger
than 10 years of age with bloody diarrhea and E. coli O157:H7 infec-
tion, approximately 15 percent will develop STEC-HUS with the acute
DEFINITION AND HISTORY onset of microangiopathic hemolytic anemia, thrombocytopenia, and
HUS refers to thrombotic microangiopathy that mainly affects the renal injury an average of 7 days (range: 5 to 13 days) after the start of
kidney and usually causes oliguric or anuric renal failure. Ingestion of diarrhea. 120

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