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Chapter 134 Thrombotic Thrombocytopenic Purpura and the Hemolytic Uremic Syndromes 1993

persisting for more than 1 year after the initial episode of TMA is incidental events. Affected patients have a high risk for recurrence
likewise associated with progressive renal disease. after renal allografting, and HUS occasionally presents in related
donors after surgery. The disorder may resemble TMA associated
with pregnancy, cancer, and chemotherapy, which have similar clini-
Therapy cal presentations, but different natural histories.

Treatment of STEC-HUS is supportive. Volume expansion within
the first 4 days of the onset of diarrhea significantly reduces the Epidemiology
incidence of progression to oliguric HUS. However, no therapy has
been shown to prevent HUS or to reduce the severity of kidney injury aHUS is a systemic TMA in which renal failure develops in the
once established. In randomized trials, neither plasma infusion nor absence of a coexisting disease. While historically considered a
exchange was of benefit in children or adults with STEC-HUS. pediatric disease, approximately 40% of cases present in adulthood,
Corticosteroids, heparin, urokinase, aspirin, dipyridamole, antifibri- with the remaining 60% occurring in pediatric patients. However,
nolytic drugs and intravenous immunoglobulin are ineffective. aHUS only accounts for 5% to 10% of all childhood HUS. Seventy
Antimotility agents and narcotics delay clearance of E. coli and toxin percent of children have their first episode before 2 years of age, 25%
from the gastrointestinal tract and may increase the risk for progres- of these developing before 6 months, an age at which STEC-HUS is
sion to TMA; therefore these agents should be avoided. Nonsteroidal very uncommon. Childhood aHUS is equally prevalent in males and
antiinflammatory agents may reduce renal blood flow and should also females, with a slight female preponderance in adults. Abnormalities
be avoided. Most experts believe that antibiotics increase the risk for in complement regulation, most commonly arising from mutations
progression to HUS, probably by lysing bacteria, releasing Stx and in complement regulatory proteins, have been implicated in up to
inducing bacteriophages on which Stx genes are expressed. Therefore, 70% of cases. Inheritance is autosomal dominant with approximately
routine use of antibiotic is discouraged. 50% penetrance, and aHUS may occur in siblings with or without
Activation of complement may contribute to the pathogenesis of identical genetic abnormalities. Clinical conditions that increase
STEC-HUS. In support of this concept, eculizumab, an antibody to complement activation (including pregnancy) may unmask the
complement factor 5, was reported to reverse neurologic abnormali- genetic propensity to develop aHUS. An autosomal recessive form of
ties, low platelet counts, and elevated LDH levels in three patients aHUS attributable to defects in the gene encoding for DGKE (an
with STEC-HUS. However, insufficient data are available to validate enzyme involved in intracellular signaling) has recently been described.
this hypothesis. During the 2011 German O105H4 STEC-HUS Defects in DGKE may account for up to 30% of cases of aHUS
epidemic, eculizumab was administered most commonly to patients presenting before the first year of life.
with the most severe organ compromise and often late in the course The incidence of aHUS in the United States has been estimated
of disease. The outcome in these patients was similar to that in at 2 per million. More than 1000 patients with aHUS investigated
untreated patients, suggesting a potential role. Similarly immunoad- for complement abnormalities have been identified through registries
sorption appeared to potentially benefit a small cohort of patients in Europe and the United States.
with severe neurologic compromise; however, most of these patients
also received other therapeutic interventions. Additional data on the
utility of eculizumab and immunoadsorption are needed before their Pathobiology
routine use can be recommended.
Isolation of patients with STEC-HUS should be considered The complement system is an ancient defense mechanism that stimu-
because shedding of the pathogenic bacteria may continue long after lates the inflammatory response and destroys pathogens by opsoniza-
cessation of diarrhea. tion or lysis. Most commonly, aHUS is a consequence of aberrant
activation of the complement AP, which leads to endothelial damage,
and is the result of mutations that lead to loss or functional impair-
ATYPICAL HEMOLYTIC UREMIC SYNDROME ment of complement regulatory proteins, or less commonly, activat-
ing mutations in alternative complement proteins.
Clinical Manifestations Complement may be activated via the classical pathway, AP or
lectin pathways. The AP plays an important role in protecting the
Like TTP, aHUS may present with a prodrome suggestive of an intravascular space against bacterial infection and depends on potent
upper respiratory tract infection or with nonspecific symptoms of amplification loops (Fig. 134.6). The AP is in a constant low-level
malaise and fatigue. Though aHUS is generally not associated with activation state because of spontaneous hydrolysis of the thioester
a prodrome of bloody diarrhea, a history of recent gastroenteritis bond in C3, and regulation by complement inhibitory proteins is
may be obtained from up to 30% of patients making distinction required to prevent pathologic activation and complement-mediated
from STEC-HUS difficult. Extrarenal manifestations may occur in injury to host tissues. C3b is deposited on cell membranes of both
up to half of the patients; neurologic manifestations are typically less pathogens and host cells. An amplification loop consisting of comple-
common and severe than in TTP and are less likely to dominate the ment factor B, factor D, and properdin leads to the deposition of
course. Evidence of microangiopathy on the peripheral blood film is a additional C3b on the cell surface and the generation of C3b conver-
universal finding, and the reticulocyte count and LDH concentration tase (C3bBbP), which further amplifies C3b generation. In the pres-
are elevated, but severe thrombocytopenia is less common than in ence of additional C3b, this convertase can cleave C5 to C5a and C5b,
TTP. Renal involvement is more severe than in TTP, with up to 60% leading to formation of the lytic C5b-C9 complex. To protect host
of patients requiring dialysis. It has been suggested that in the absence cells from collateral damage as a consequence of complement activa-
of another cause for a renal TMA (such as STEC-HUS, systemic tion, multiple soluble and membrane-associated regulatory proteins
lupus erythematosus, scleroderma, medication effect, complications inactivate C3b on the cell surface. These include plasma protein factor
of transplantation, etc.), the presence of a creatinine over 2.3 mg/ H and membrane-associated cofactor protein (MCP; CD46), both of
dL and a platelet count over 30,000/µL argues against a diagnosis of which bind to membrane bound C3b. Then another plasma protein,
TTP and favors aHUS. However, cohort studies in patients with TTP factor I (CFI), cleaves and inactivates C3b. Similarly, cell-surface
indicated that some patients did require dialysis; suggesting that these thrombomodulin enhances CFI-mediated inactivation of C3b.
disorders may be indistinguishable on clinical grounds alone, thereby Another membrane-associated protein, decay-accelerating factor
highlighting the importance of ADAMTS13 assessment. (DAF; CD55) accelerates the inactivation of C3 convertase, although
Typically, aHUS follows a chronic relapsing course, often compli- mutations of DAF have not been shown to play a role in aHUS.
cated by hypertension and renal insufficiency. Moreover, exacerba- Mutations in several complement regulatory proteins predispose
tions are often preceded by infection, pregnancy, or other seemingly to aHUS. Mutations in CFH account for 25% of cases. Loss of