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

LABORATORY FEATURES than expected may be required for adequate volume replacement, and
Aside from signs of dehydration or electrolyte imbalances from diar- monitoring for fluid overload and hypertension is essential. A rising
rhea or vomiting, laboratory testing may be unremarkable before platelet count signals the end of the period of risk for developing HUS.
bloody diarrhea develops. Thrombocytopenia and hemolysis with For patients with HUS, hemolysis can persist as the HUS resolves and
associated laboratory abnormalities develop after bloody diarrhea and require additional red cell transfusions.
usually before renal failure. The platelet count falls to an average of Extrarenal involvement is common, although the incidence of spe-
40 × 10 /L. Renal signs may include a rising creatinine, proteinuria, cific complications varies widely. Depending on the outbreak, central
9
hematuria, hypertension, and oliguria or anuria. Usually the PT and nervous system involvement (seizures, coma, or stroke) occurs in 10 to
aPTT are normal or minimally prolonged, plasma fibrinogen is normal 65 percent of cases and is more common in older patients. Cardiac dys-
or elevated, and fibrin degradation products may be moderately ele- function is associated with ischemia or congestive heart failure. Patients
vated. 120,123 ADAMTS13 levels are normal. 124,125 may require mechanical ventilation for seizures, coma, pulmonary
Stool should be cultured on selective media for E. coli O157:H7 edema, or pneumonia. Gastrointestinal involvement can include hem-
and tested for Stxs to detect non–O157 strains. STEC in the stool are orrhagic colitis, necrosis, perforation, peritonitis, pancreatitis, diabetes
120,128,129
found in at least 90 percent of patients during the first 6 days but in less mellitus, and rectal prolapse.
than 30 percent of patients at later times. Fecal leukocytes are not always The incidence of death and end-stage renal failure also varies
present and generally are not abundant. 120 widely, but correlates with the need for initial dialysis and central ner-
Serologic testing for antibodies to STEC surface antigens at diag- vous system involvement. In a meta-analysis of more than 3400 patients
nosis and after 2 weeks can facilitate the diagnosis of STEC-HUS if stool with STEC-HUS, an average of 9 percent died and 3 percent devel-
cultures are not informative. Titers rise after infection and persist for oped permanent end-stage renal failure 1 or more years later. Another
8 to 12 weeks. 25 percent had persistent hypertension, proteinuria, or chronic renal
130
STEC-HUS mainly affects the renal cortex, which often shows insufficiency.
extensive necrosis. Lesions occur less frequently in the pancreas, brain, Inability to detect STEC may not strongly affect the clinical course.
adrenal glands, and myocardium. The thrombi of HUS typically involve In a study of 268 patients with HUS, 59 percent had prodromal diarrhea
glomerular capillaries and arterioles and are composed mainly of fibrin plus bacteriologic or serologic evidence of infection by STEC; 21 per-
and red cells with few platelets. 47,126 cent had only diarrhea, and 10 percent had only positive bacteriologic
or serologic studies. All three groups had similar outcomes: approxi-
mately 1 percent died and 73 percent recovered normal renal function.
DIFFERENTIAL DIAGNOSIS In contrast, the 11 percent of patients with neither diarrhea nor docu-
mented STEC infection had a significantly worse outcome; 10 percent
Unlike STEC-HUS, bloody diarrhea caused by Salmonella, Shigella, or died and only 34 percent recovered normal renal function. Most of
121
Clostridium difficile is likely to be accompanied by fever and prostration. these latter patients probably had “atypical hemolytic uremic syndrome
Coinfection with STEC and C. difficile can occur. Otherwise the differ- (aHUS),” which has a distinct cause and prognosis.
ential diagnosis of apparent STEC-HUS includes unusual presentations
of other causes of thrombotic microangiopathy (see Table 132–1).
ATYPICAL HEMOLYTIC UREMIC

THERAPY SYNDROME
Patients with acute bloody diarrhea should be admitted to the hospital
for diagnosis and management of presumed STEC infection as well as DEFINITION AND HISTORY
infection control. Early intravenous hydration to maintain renal perfu- Diarrhea-negative or aHUS is not associated with diarrhea or Stx-
sion protects against the development of HUS. Most patients require producing organisms and occurs in patients without an obvious predis-
120
red cell transfusions. Daily monitoring of hemoglobin, platelet count, posing condition.
electrolytes, blood urea nitrogen (BUN), and creatinine is important. Reporting on patients seen in southern Africa in 1965, Bar-
The risks and benefits of antibiotic use in STEC-HUS may depend nard and Kibel first distinguished typical diarrhea-associated HUS
on the stage of illness. Antibiotics should not be used early in the course from “atypical” patients who did not have diarrhea. In the 1970s,
131
of acute diarrheal illness caused by E. coli O157:H7 because antibiotics Kaplan proposed that recurrent familial cases of HUS represented a
increase the risk of HUS. However, retrospective analysis of a 2011 distinct genetic illness. 132,133 By 1993, aHUS was an accepted diagno-
127
outbreak of E. coli O104:H4 infection suggests that treatment with mul- sis of uncertain cause, although increased consumption of com-
134
tiple antibiotics after the development of HUS may have reduced the plement C3 and deficiency of factor H had been described in some
incidence of seizures and death. 128 patients. In 1998, Warwicker and colleagues showed that muta-
135
Antimotility agents and narcotics increase the risk of HUS and tions in complement factor H (CFH) caused familial HUS, and
136
neurologic complications. Nonsteroidal antiinflammatory drugs and mutations in other proteins of the alternative complement pathway
antihypertensives that reduce renal perfusion such as angiotensin-con- quickly followed. These results provided a rationale for treating
verting enzyme inhibitors and angiotensin receptor blockers should be aHUS with inhibitors of complement activation, which has proved
avoided. No convincing data indicate that antiplatelet agents, anticoag- very effective. 137
ulants, plasma exchange, glucocorticoids, rituximab, or an inhibitor of
the terminal components of complement, eculizumab, add benefit to ETIOLOGY AND PATHOGENESIS
supportive therapy and dialysis, for children or adults. 58,120,128
The alternative complement pathway drives the pathogenesis of aHUS.
Complement component C3 is spontaneously converted to C3b at a
COURSE AND PROGNOSIS low rate and deposited on cell surfaces. Under normal circumstances
Patients often have a degree of diffuse vascular injury and may become this C3b is promptly cleaved and inactivated by the serine protease
edematous with intravenous hydration. Consequently more sodium factor I, and this reaction is accelerated by factor H or membrane

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